2-isoxazoline derivative and process for producing the same, and process for producing related derivatives from the same

ABSTRACT

The present invention provides useful intermediates for the synthesis of 2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives which serve as intermediates in the synthesis of medicines such as retrovirus protease inhibitors including human immunodeficiency virus (HIV) protease inhibitors, and a method for preparing these intermediates using the former intermediates. 
     More particularly, the invention provides methods for preparing a 2-isoxazoline derivative represented by formula  1! and a 2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivative obtainable by reducing the 2-isoxazoline derivative and represented by formula  6!: ##STR1## (wherein Ph is phenyl; and each of R 1  and R 2  independently represents hydrogen, acyl, alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl, alkyl, arylalkyl, aryl, alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, or R 1  and R 2  are linked to each other to represent divalent acyl).

This is a division of application Ser. No. 08/702,582, filed May 25,1995, now U.S. Pat. No. 5,750,717, which in turn is a §371 applicationof PCT/JP95/00331 filed in Japan on Mar. 2, 1995.

TECHNICAL FIELD

The present invention relates to novel 2-isoxazoline derivatives andacid addition salts thereof, and a method for preparing the derivativesand salts. The invention also relates to a method for preparing relatedderivatives by reducing the 2-isoxazoline derivatives.

More particularly, the present invention relates to novel 2-isoxazolinederivatives and acid addition salts thereof, which are usefulintermediates for synthesizing 2,5-diamino-1,6-diphenyl-3-hydroxyhexanederivatives which in turn serve as intermediates in the synthesis ofmedicines such as retrovirus protease inhibitors including humanimmunodeficiency virus (HIV) protease inhibitors, and to a method forpreparing the derivatives and salts. The invention also relates to amethod for preparing 2,5-diamino-1,6-diphenyl-3-hydroxyhexanederivatives using the novel 2-isoxazoline derivatives.

BACKGROUND ART

(2S,3S,5S)-2,5-Diamino-1,6-diphenyl-3-hydroxyhexane derivatives areknown to be useful as intermediates for retrovirus protease inhibitors(JP-A-4-308574, International Publication No. WO94/14436, etc.). Methodsfor synthesizing the derivatives are known, including a method in which(2S,3R,4S,5S)-3-acetoxy-2,5-bis-(N-benzyloxycarbonylamino)-4-bromo-1,6-diphenylhexanederived from N-benzyloxycarbonyl-L-phenylalaninal is reacted withtri-n-butyltin hydride and 2,2'-azobis(2-methylpropionitrile) to give(2S,3S,5S)-3-acetoxy-2,5-bis(N-benzyloxycarbonylamino)-1,6-diphenylhexane(JP-A-4-308574 and International Publication No. WO94/14436, referred toas synthesizing method A), a method in which(2S,4S,5S)-5-tert-butoxycarbonylamino-4-tert-butyldimethylsilyloxy-6-phenyl-2-(phenylmethyl)hexanoicacid is reacted, in the presence of triethylamine, with diphenylphosphorazidate (PhO)₂ P(O)N₃ ! and further with benzyl alcohol to give(2S,3S,5S)-2-tert-butoxycarbonylamino-3-tert-butyldimethylsilyloxy-5-benzyloxycarbonylamino-1,6-diphenylhexane(J. Org. Chem., 1993, 58, 1025, referred to as synthesizing method B), amethod in which(2S,4S,5S)-5-tert-butoxycarbonylamino-4-tert-butyldimethylsilyloxy-6-phenyl-2-(phenylmethyl)hexanoicacid is reacted, in the presence of triethylamine, with diphenylphosphorazidate (PhO)₂ P(O)N₃ ! and further with 3-pyridylcarbinol togive(2S,3S,5S)-2-tert-butoxycarbonylamino-3-tert-butyldimethylsilyloxy-5-(3-pyridylmethoxycarbonylamino)-1,6-diphenylhexane(J. Org. Chem., 1993, 58, 1025 and Tetrahedron, 1993, 49, 8739, referredto as synthesizing method C), a method in which(5S)-2-amino-5-(N,N-dibenzylamino)-4-oxo-1,6-diphenylhexa-2-ene is firstreacted with sodium borohydride which has been treated withmethanesulfonic acid and further reacted with sodium borohydride whichhas been treated with trifluoroacetic acid to give(2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane(International Publication No. WO94/14436 and J. Org. Chem., 1994, 59,4040, referred to as synthesizing method D), and a method in which(5S)-2-(tert-butoxycarbonylamino)-5-(N,N-dibenzylamino)-1,6-diphenyl-4-oxo-2-hexeneis first reacted with diborane tetrahydrofuran complex and furtherreacted with lithium aluminum hydride or potassium borohydride to give(2S,3S,5S)-2-N,N-dibenzylamino-5-(tert-butoxycarbonylamino)-3-hydroxy-1,6-diphenylhexane(International Publication No. W094/14436, referred to as synthesizingmethod E).

However, synthesizing method A (JP-A-4-308574) has drawbacks that ituses heavy metal reagents such as vanadium, zinc, and tin in thesynthesis route including the synthesis of starting materials and thatthe reaction must be carried out at an extremely low temperature.

Synthesizing method B (J. Org. Chem., 1993, 58, 1025) and synthesizingmethod C (J. Org. Chem., 1993, 58, 1025 and Tetrahedron, 1993, 49, 8739)have drawbacks that they use a special reagent, diphenyl phosphorazidate(PhO)₂ P(O)N₃ ! in the synthesis route including the synthesis ofstarting materials, and that the reaction must be carried out at anextremely low temperature.

Synthesizing method D (International Publication No.

W094/14436 and J. Org. Chem., 1994, 59, 4040) and synthesizing method E(International Publication No. WO94/14436) have the drawback that thereaction must be carried out at an extremely low temperature in thesynthesis route including the synthesis of starting materials.

Under the above circumstances, it has been desired to develop apractical method for synthesizing2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives which eliminatesthe necessity of heavy metal reagents, special reagents, and extremelylow temperatures for reaction.

The present inventors carried out extensive studies, and found novel2-isoxazoline derivatives and acid addition salts thereof, which arevery useful intermediates for 2,5-diamino-1,6-diphenyl-3-hydroxyhexanederivatives which in turn serve as intermediates in the synthesis ofmedicines such as retrovirus protease inhibitors, a method for preparingthe derivatives and salts, and a method for preparing2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives using the novel2-isoxazoline derivatives.

DISCLOSURE OF THE INVENTION

Accordingly, the present invention provides a 2-isoxazoline derivativerepresented by the following formula 1!, an acid addition salt thereof,and a method for preparing the derivative and salt: ##STR2## (wherein Phrepresents phenyl; and each of R¹ and R² independently representshydrogen, acyl, alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl, alkyl,arylalkyl, aryl, alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, orR¹ and R² are linked to each other to represent divalent acyl).

The present invention also provides a mixture of 2-isoxazolinederivatives represented by the following formulas 2! and 3!, a mixtureof acid addition salts thereof, that is, an acid addition salt of themixture, and a method for preparing the mixture and the mixture of thesalts: ##STR3## (wherein Ph represents phenyl; and each of R¹ and R²independently represents hydrogen, acyl, alkyloxycarbonyl,arylalkyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylalkylaminocarbonyl, arylaminocarbonyl, alkyl, arylalkyl, aryl,alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, or R¹ and R² arelinked to each other to represent divalent acyl).

The present invention also provides a 2-isoxazoline derivativerepresented by the following formula 2!, an acid addition salt thereof,and a method for preparing the derivative and salt: ##STR4## (wherein Phrepresents phenyl; and each of R¹ and R² independently representshydrogen, acyl, alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl, alkyl,arylalkyl, aryl, alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, orR¹ and R² are linked to each other to represent divalent acyl).

The present invention also provides a method for preparing a2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivative represented by thefollowing formula 6! characterized by reducing a3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline derivativerepresented by formula 1!: ##STR5## (wherein Ph represents phenyl; andeach of R¹ and R² independently represents hydrogen, acyl,alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl, alkyl,arylalkyl, aryl, alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, orR¹ and R² are linked to each other to represent divalent acyl).

The present invention also provides a method for preparing a(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivativerepresented by the following formula 7! and/or a(2S,3S,5R)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivativerepresented by the following formula 8! characterized by reducing a(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinederivative represented by formula 2!: ##STR6## (wherein Ph representsphenyl; and each of R¹ and R² independently represents hydrogen, acyl,alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl, alkyl,arylalkyl, aryl, alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, orR¹ and R² are linked to each other to represent divalent acyl).

DESCRIPTION OF PREFERRED EMBODIMENTS

Since the 2-isoxazoline derivatives of the present invention have anasymmetric carbon atom at the 5-position of a 2-isoxazoline ring, andhave an asymmetric carbon atom at the 1'-position of the substituent,1'-amino-2'-phenyl ethyl (or a group having a substituent on the Natom), which is the substituent at the 5-position of the 2-isoxazolinering, they assume the following four stereoisomers: (5R,1'R), (5S,1'S),(5R,1'S), and (5S,1'R). Accordingly, the 2-isoxazoline derivatives ofthe present invention may be present as stereoisomers corresponding tothe above situations, and may also be present as mixtures of thestereoisomers in arbitrary ratios. In this specification, it must beunderstood that each derivative encompasses four stereoisomers and amixture of them in an arbitrary ratio.

In the above formulas 1!, 2!, and 3!, R¹ and R² are arbitrarily andindependently selected from the group consisting of hydrogen, acyl,alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl, alkyl,arylalkyl, aryl, alkylsulfonyl, arylalkylsulfonyl, and arylsulfonyl.Alternatively, like a phthaloyl group, R¹ and R² may be linked to eachother to form a divalent acyl group for cyclizing the group. In thenovel 2-isoxazoline derivatives represented by formulas 1!, 2!, or 3!,it is particularly preferred that at least one of R¹ and R² be hydrogenor that R¹ and R² are both arylalkyl.

When R¹ or R² is acyl or when R¹ and R² are linked to each other to formdivalent acyl, specific examples of R¹ or R² include formyl, acetyl,propionyl, 2-methylpropionyl, 2,2-dimethylpropionyl, benzoyl,p-methylbenzoyl, p-methoxybenzoyl, p-nitrobenzoyl, phenylacetyl,2-pyridylmethoxycarbonylvalyl, 3-pyridylmethoxylcarbonylvalyl,4-pyridylmethoxycarbonylvalyl, 2-pyridylmethylaminocarbonylvalyl,6-methyl-2-pyridylmethylaminocarbonylvalyl,2-pyridylmethylaminocarbonylisoleucyl, phthaloyl, succinyl, and maleoyl.

When R¹ or R¹ is acyl or when R¹ and R² are linked to each other to formdivalent acyl, specific examples of resulting compounds include3-phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-acetylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1-propionylamino-² '-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(2"-methylpropionyl)amino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(2',2'-dimethylpropionyl)amino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-benzoylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methylbenzoylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methoxybenzoylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-nitrobenzoylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-phenylacetylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(2"-pyridylmethoxycarbonyl)valylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(3'-pyridylmethoxycarbonyl)valylamino-b2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(4"-pyridylmethoxycarbonyl)valylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(N-methyl-N-(2"-pyridyl)methyl)aminocarbonylvalylamino-2'-phenylethyl)-2isoxazoline,3-phenylmethyl-5-(1'-(N-methyl-N-(6"-methyl-2"-pyridyl)methyl)aminocarbonylvalylamino-2-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(N-methyl-N-(2"-pyridyl)methyl)aminocarbonylisoleucylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-succinimido-2'-phenylethyl)-2-isoxazoline, and3-phenylmethyl-5-(1'-maleimido-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is alkyloxycarbonyl, specific examples of R¹ or R² includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,sec-butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.

When R¹ or R² is alkyloxycarbonyl, specific examples of resultingcompounds include3-phenylmethyl-5-(1'-methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-ethoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-propoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-isopropoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-sec-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-isobutoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,and3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is arylalkyloxycarbonyl, specific examples of R¹ or R²include benzyloxycarbonyl, p-methylphenylmethoxycarbonyl,p-methoxyphenylmethoxycarbonyl, 2-pyridylmethoxycarbonyl,3-pyridylmethoxycarbonyl, 4-pyridylmethoxycarbonyl,1-(3'-pyridyl)ethoxycarbonyl, 2-thiazolylmethoxycarbonyl,4-thiazolylmethoxycarbonyl, 5-thiazolylmethoxycarbonyl,pyrazinylmethoxycarbonyl, 2-furanylmethoxycarbonyl, and3-furanylmethoxycarbonyl.

When R¹ or R² is arylalkyloxycarbonyl, specific examples of resultingcompounds include3-phenylmethyl-5-(1-benzyloxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methylphenylmethoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methoxyphenylmethoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(2"-pyridyl)methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(3"-pyridyl)methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(4"-pyridyl)methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(1"-(3'"-pyridyl)ethoxy)carbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(2"-thiazolyl)methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(4"-thiazolyl)methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(5"-thiazolyl)methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-pyrazinylmethoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(2"-furanyl)methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,and 3-phenylmethyl-5-(1'-(3"-furanyl)methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is aryloxycarbonyl, specific examples of R¹ or R² includephenoxycarbonyl, p-methylphenoxycarbonyl, p-methoxyphenoxycarbonyl,p-nitrophenoxycarbonyl, 1-naphthyloxycarbonyl, and2-naphthyloxycarbonyl.

When R¹ or R² is aryloxycarbonyl, specific examples of resultingcompounds include3-phenylmethyl-5-(1'-phenoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methylphenoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methoxyphenoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-nitrophenoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(1"-naphthyl)oxycarbonylamino-2'-phenylethyl)-2-isoxazoline,and3-phenylmethyl-5-(1'-(2"-naphthyl)oxycarbonylamino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is alkylaminocarbonyl, specific examples of R¹ or R²include methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl,and isopropylaminocarbonyl.

When R¹ or R² is alkylaminocarbonyl, specific examples of resultingcompounds include3-phenylmethyl-5-(1'-methylaminocarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-ethylaminocarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-propylaminocarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-isopropylaminocarbonylamino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is arylalkylaminocarbonyl, specific examples of R¹ or R²include benzylaminocarbonyl, 2-pyridylmethylaminocarbonyl,3-pyridylmethylaminocarbonyl, and 4-pyridylmethylaminocarbonyl.

When R¹ or R² is arylalkylaminoarbonyl, specific examples of resultingcompounds include3-phenylmethyl-5-(1-benzylaminocarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1-(2'-pyridyl)methylaminocarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(3"-pyridyl)methylaminocarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(4"-pyridyl)methylaminocarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(N-methyl-N-(2"-pyridylmethyl))aminocarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(N-methyl-N-(3"-pyridylmethyl))aminocarbonylamino-2'-phenylethyl)-2-isoxazoline,and3-phenylmethyl-5-(1'-(N-methyl-N-(4"-pyridylmethyl))aminocarbonylamino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is arylaminocarbonyl, specific examples of R¹ or R²include phenylaminocarbonyl and p-methoxyphenylaminocarbonyl.

When R¹ or R 2 is arylaminocarbonyl, specific examples of resultingcompounds include3-phenylmethyl-5-(1'-phenylaminocarbonylamino-2'-phenylethyl)-2-isoxazolineand 3-phenylmethyl-5-(1'-p-methoxyphenylaminocarbonylamino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is alkyl, specific examples of R¹ or R² include methyl,ethyl, propyl, and isopropyl.

When R¹ or R² is alkyl, specific examples of resulting compounds include3-phenylmethyl-5-(1'-methylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-ethylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-propylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-isopropylamino-2'-phenylethyl)-2-isoxazoline, aswell as those listed hereinabove for cases in which R¹ or R² is acylincluding3-phenylmethyl-5-(1'-(N-methyl-N-(2'-pyridyl)methyl)aminocarbonylvalylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(N-methyl-N-(6'-methyl)-2"-pyridyl)methyl)aminocarbonylvalylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(N-methyl-N-(2'-pyridyl)methyl)aminocarbonylisoleucylamino-2'-phenylethyl)-2-isoxazoline,and in addition, those listed hereinabove for cases in which R¹ or R² isarylalkylaminocarbonyl including3-phenylmethyl-5-(1'-(N-methyl-N-(2'-pyridylmethyl))aminocarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-(N-methyl-N-(3"-pyridylmethyl))aminocarbonylamino-2'-phenylethyl)-2-isoxazoline, and3-phenylmethyl-5-(1'-(N-methyl-N-(4"-pyridylmethyl))aminocarbonylamino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is arylalkyl, specific examples of R¹ or R² includebenzyl, p-methoxyphenylmethyl, p-methoxyphenylmethyl, andp-nitrophenylmethyl.

When R¹ or R² is arylalkyl, specific examples of resulting compoundsinclude 3-phenylmethyl-5-(1'-benzylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methylphenylmethylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1-p-methoxyphenylmethylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-nitrophenylmethylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-N,N-dibenzylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-N,N-bis(p-methylphenylmethyl)amino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-N,N-bis(p-methoxyphenylmethyl)amino-2'-phenylethyl)-2-isoxazoline,and3-phenylmethyl-5-(1'-N,N-bis(p-nitrophenylmethyl)amino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is aryl, specific examples of R¹ or R² include phenyl,p-methylphenyl, p-methoxyphenyl, and p-nitrophenyl.

When R¹ or R² is aryl, specific examples of resulting compounds include3-phenylmethyl-5-(1'-phenylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methylphenylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methoxyphenylamino-2'-phenylethyl)-2-isoxazoline,and3-phenylmethyl-5-(1'-p-nitrophenylamino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is alkylsulfonyl, specific examples of R¹ or R² includemethylsulfonyl, ethylsulfonyl, propylsulfonyl, and isopropylsulfonyl.

When R¹ or R² is alkylsulfonyl, specific examples of resulting compoundsinclude3-phenylmethyl-5-(1'-methylsulfonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-ethylsulfonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-propylsulfonylamino-2'-phenylethyl)-2-isoxazoline,and3-phenylmethyl-5-(1'-isopropylsulfonylamino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is arylalkylsulfonyl, specific examples of R¹ or R²include benzylsulfonyl, p-methylphenylmethylsulfonyl,p-methoxyphenylmethylsulfonyl, and p-nitrophenylmethylsulfonyl.

When R¹ or R² is arylalkylsulfonyl, specific examples of resultingcompounds include3-phenylmethyl-5-(1'-benzylsulfonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methylphenylmethylsulfonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methoxyphenylmethylsulfonylamino-2'-phenylethyl)-2-isoxazoline,and3-phenylmethyl-5-(1'-p-nitrophenylmethylsulfonylamino-2'-phenylethyl)-2-isoxazoline.

When R¹ or R² is arylsulfonyl, specific examples of R¹ or R² includephenylsulfonyl, p-methylphenylsulfonyl, p-methoxyphenylsulfonyl, andp-nitrophenylsulfonyl.

When R¹ or R² is arylsulfonyl, specific examples of resulting compoundsinclude3-phenylmethyl-5-(1'-phenylsulfonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methylphenylsulfonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-p-methoxyphenylsulfonylamino-2'-phenylethyl)-2-isoxazoline,and3-phenylmethyl-5-(1'-p-nitrophenylsulfonylamino-2'-phenylethyl)-2-isoxazoline.

Acid addition salts of the 2-isoxazoline derivatives of the presentinvention may be arbitrarily selected from the salts derived fromreactions with inorganic acids or organic acids. Acid addition salts mayalso be adducts with an organic solvent or water at an arbitrary molarratio. The molar ratio of a novel 2-isoxazoline derivative representedby formula 1!, 2!, or 3! to an acid may be determined so that an acidaddition salt is obtained from the reaction of the derivative and acid.

Examples of acid addition salts derived from inorganic acids includehydrochlorides, hydrobromides, hydroiodides, sulfates, hydrogensulfates,phosphates, monohydrogenphosphates, dihydrogenphosphates, nitrates, andthiocyanates.

Examples of acid addition salts derived from organic acids includecarboxylate, sulfonate, and phosphonates. Examples of acid additionsalts derived from carboxylic acid include formates, acetates,propionates, butyrates, isobutyrates, cinnamates, benzoates,p-methylbenzoates, p-methoxybenzoates, p-nitrobenzoates, phenylacetates,lactates, oxalates, malonates, succinates, glutarates, adipates,maleates, fumarates, phthalates, terephthalates, citrates, malates,tartarates, salicylates, nicotinates, mandelates and salts from aminoacids (such as glycine, alanine, aspartic acid, and glutamic acid).Examples of acid addition salts derived from sulfonic acid includemethanesulfonates, ethanesulfonates, benzenesulfonates,p-toluenesulfonates, p-chlorobenzenesulfonates,p-bromobenzenesulfonates, 2-naphthalenesulfonates, andcamphorsulfonates. Examples of acid addition salts derived fromphosphonic acid include methylphosphonates and phenylphosphonates.

Preferred examples of the novel 2-isoxazoline derivatives of the presentinvention represented by formulas 1!, 2!, or 3! include the following:

(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline;(5RS,1'RS)-3-phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazoline;(5RS,1'RS)-3-phenylmethyl-5-(1'-acetylamino-2'-phenylethyl)-2-isoxazoline;(5RS,1'RS)-3-phenylmethyl-5-(1'-benzoylamino-2'-phenylethyl)-2-isoxazoline;(5RS,1'RS)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline;(5RS,1'RS)-3-phenylmethyl-5-(1'-benzyloxycarbonylamino-2'-phenylethyl)-2-isoxazoline;(5RS,1'RS)-3-phenylmethyl-5-(1'-methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline;(5RS,1'RS)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazoline;(5RS,1'RS)-3-phenylmethyl-5-(1'-N,N-dibenzylamino-2'-phenylethyl)-2-isoxazoline;(5RS,1'RS)-3-phenylmethyl-5-(1-amino-2'-phenylethyl)-2-isoxazolinehydrochloride;(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate;(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinebenzenesulfonate;(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-1'-phenylethyl)-2-isoxazolinemethanesulfonate;(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolineoxalate;(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinebenzoate;(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline;(5S,1'S)-3-phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazoline;(5S,1'S)-3-phenylmethyl-5-(1'-acetylamino-2'-phenylethyl)-2-isoxazoline;(5S,1'S)-3-phenylmethyl-5-(1'-benzoylamino-2'-phenylethyl)-2-isoxazoline;(5S,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline;

(5S,1'S)-3-phenylmethyl-5-(1'-benzyloxycarbonylamino-2'-phenylethyl)-2-isoxazoline;(5S,1'S)-3-phenylmethyl-5-(1'-methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline;(5S,1'S)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazoline;(5S,1'S)-3-phenylmethyl-5-(1'-N,N-dibenzylamino-2'-phenylethyl)-2-isoxazoline;(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinehydrochloride;(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate;(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinebenzenesulfonate;(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinemethanesulfonate;(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolineoxalate;(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinebenzoate;(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline(S)-mandelate; and(5R,1'R)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline(R)-mandelate.

2-isoxazoline derivatives represented by formula 1!, 2!, or 3!, or theiracid addition salts may be synthesized from other 2-isoxazolinederivatives or their acid addition salts by substitution of R¹ and/orR², neutralization, acid-addition or by combination of these procedures.

For example, when a 2-isoxazoline derivative represented by formula 1!,2!, or 3! in which at least one of R¹ and R² is hydrogen, or an acidaddition salt of such a derivative is treated with a reagent capable ofintroducing a group other than hydrogen, it is possible to obtain a2-isoxazoline derivative represented by formula 1!, 2!, or 3! or an acidaddition salt thereof in which at least one of R¹ and R² has beenconverted into a group other than hydrogen, which falls within the scopeof the present invention.

Alternatively, when a 2-isoxazoline derivative represented by formula1!, 2!, or 3! in which at least one of R¹ and R² is a group other thanhydrogen, or an acid addition salt of such a derivative is treated underconditions that permit removal of the group other than hydrogen, forexample, by treatment with an acid or a base, oxidation or reduction, itis possible to obtain a 2-isoxazoline derivative represented by formula1!, 2!, or 3! or an acid addition salt thereof in which at least thegroup other than hydrogen has been converted into hydrogen, which fallswithin the scope of the present invention.

When 2-isoxazoline derivative represented by formula 1!, 2!, or 3! isprocessed with an acid, a corresponding acid addition salt can beobtained.

Also, when an acid addition salt of 2-isoxazoline derivative representedby formula 1!, 2!, or 3! is processed with an inorganic base (such asNaOH, KOH, etc.) or an organic base (such as triethylamine,diisopropylamine, etc., that is, when the acid added to the salt isneutralized, a corresponding 2-isoxazoline derivative is obtained.

The above-mentioned treatments may be combined with one another.Illustrative examples of treatments will next be described below.

By reacting 3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinewith a formulating agent (e.g., formic acid, ethyl formate, etc.), anacetylating agent (e.g., acetic anhydride, acetyl chloride, etc.), abenzoylating agent (e.g., benzoyl chloride, etc.), a phthaloylatingagent (e.g., N-carbethoxylphthalimido, phthalic anhydride, etc.), amethoxycarbonylating agent (e.g., methyl chloroformate, dimethyldicarbonate, etc.), tert-butoxycarbonylating agent (e.g., di-tert-butyldicarbonate, etc.), a benzyloxycarbonylating agent (e.g., benzylchloroformate, etc.), or with a benzylating agent (e.g., benzylchloride, benzyl bromide, etc.), it is possible to obtain corresponding3-phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-acetylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-benzoylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-benzyloxycarbonylamino-2'-phenylethyl)-2-isoxazoline,and3-phenylmethyl-5-(1'-N,N-dibenzylamino-2'-phenylethyl)-2-isoxazoline.

Also, by treating3-phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazoline,3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline,or3-phenylmethyl-5-(1'-benzyloxycarbonylamino-2'-phenylethyl)-2-isoxazoline,with an acid such as hydrochloric acid, trifluoroacetic acid, orp-toluenesulfonic acid, and then with a base,3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline can beobtained.

By treating3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazoline withhydrazine, methylamine, etc.,3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline can beobtained.

By treating 3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinewith hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid,methanesulfonic acid, oxalic acid, benzoic acid, (S)-mandelic acid, or(R)-mandelic acid, it is possible to obtain corresponding3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline hydrochloride,3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate,3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinebenzenesulfonate,3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinemethanesulfonate,3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline oxalate,3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline benzoate,3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline (S)-mandelate,or 3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline(R)-mandelate. When these acid addition salts are treated with aninorganic base such as NaOH or an organic base such as triethylamine,3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline can beobtained.

By treating3-phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazoline or3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolinewith hydrochloric acid or p-toluenesulfonic acid,3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline hydrochlorideor 3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate can be obtained.

The novel 2-isoxazoline derivatives represented by formula 1!, 2!, or 3!can be synthesized by reacting a compound of formula 4! or 5! withphenylacetonitrile oxide. ##STR7## (wherein Ph represents phenyl; andeach of R¹ and R² independently represents hydrogen, acyl,alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl, alkyl,arylalkyl, aryl, alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, orR¹ and R² are linked to each other to represent divalent acyl).

The compounds of 4! or 5! can be synthesized using known methods. Forexample, it is known that(S)-3-tert-butoxycarbonylamino-4-phenyl-1-butene can be obtained fromthe reaction of (S)-tert-butoxycarbonylphenylalaninal and methylidenetriphenylphosphorane which is obtainable from a reaction usingmethyltriphenylphosphonium bromide and a base such as butyl lithium(see, for example, JP-A-61-33152, J. Org. Chem., 1987, 52, 1487, andJP-A-2-191243). Also, it is known that (S)-3-amino-4-phenyl-1-butene canbe obtained by reacting(2RS,3S)-2-hydroxy-3-tert-butoxycarbonylamino-4-phenyl-1-trimethylsilylbutanewith an ether complex of boron trifluoride (see, for example,JP-A-4-257520 and J. Med. Chem., 1992, 35, 1685). It is also known that3-trichloroacetylamino-4-phenyl-1-butene can be obtained by heating, inxylene, trichloroacetoimidato obtained from the reaction of4-phenyl-2-butene-1-ol and trichloroacetonitrile (see, for example,JP-A-61-22055 and J. Chem. Soc. Chem. Commun., 1984, 770). Moreover, itis known that 3-benzylamino-4-phenyl-1-butene can be obtained byreacting 3-benzylamino-4-phenyl-1-butyne with hydrogen in the presenceof a Lindlar catalyst (J. Chem. Soc. Perkin Trans. 1, 1983, 387).Furthermore, it is known that(S)-3-tert-butoxycarbonylamino-4-phenyl-1-butene can be obtained byreacting(S)-3-tert-butoxycarbonylamino-4-phenylbutylo-nitrophenylselenide withaqueous hydrogen peroxide (Heterocycles, 1989, 29, 1835).

On the other hand, phenylacetonitrile oxide can be synthesized by aconventional method for synthesizing nitrile oxide, e.g., by a methoddescribed in Kurt B. G. Torssell, "Nitrile Oxides, Nitrones, andNitronates in Organic Synthesis" (VCH Publishers, Inc., New York, 1988).

It is known that phenylacetonitrile oxide can be obtained by reactingphenylacetohydroximoyl chloride with triethylamine (see, for example,Gazz. Chim. Ital., 1980, 110, 341 and J. Org. Chem., 1988, 53. 2426). Itis also known that phenylacetonitrile oxide can be obtained by reacting2-phenylnitroethane with phenylisocyanate in the presence oftriethylamine (J. Chem. Soc. Chem. Commun., 1982, 291). It is also knownthat phenylacetonitrile oxide can be obtained by reactingphenylacetoaldehyde oxime with dimethyldioxirane (Journal of theChemical Society of Japan, Chemistry and Industrial Chemistry, 1992,420).

Although it is possible to perform the reaction of a compound 4! or 5!and phenylacetonitrile oxide after phenylacetonitrile oxide is isolated,phenylacetonitrile oxide generated in situ may be reacted with acompound 4! or 5!, because phenylacetonitrile oxide is unstable as arethe case with nitrile oxides in general. In view of the yield ofreaction and operability, it is advantageous to react phenylacetonitrileoxide generated in situ.

Suitable methods for generating phenylacetonitrile oxide include amethod in which a precursor of phenylacetonitrile oxide (for example,phenylacetohydroximoyl chloride, 2-phenylnitroethane, andphenylacetaldehyde oxime) or the other reagents (for example,triethylamine, phenylisocyanate, and dimethyldioxirane) are added to thereaction system at a suitable rate.

The compounds 4! or 5! which are reacted with phenylacetonitrile oxideare not particularly limited so long as side reactions are negligible inpractice. In order to avoid side reactions between --NR¹ R² at the3-position of compound 4! or 5! and phenylacetonitrile oxide, it ispreferred that at least one of R¹ and R² be an electron attractivegroup, or that R¹ and R² are both groups other than hydrogen. Examplesof R¹ and R² of compounds 4! and 5! coincide with those listed forcompounds 1!. In cases where at least one of R¹ or R² is an electronattractive group, examples of preferred species of R¹ and R² includeacyl, alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl,alkylsulfonyl, arylalkylsulfonyl, and arylsulfonyl, and those pairs ofR¹ and R² which link to each other to form a divalent acyl group. Inview of readiness of post-treatment of reaction, preferred R¹ and R² areacyl, alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl, and apair of R¹ and R² which link to each other to form a divalent acylgroup.

If R¹ and R² are both groups other than hydrogen, no particularlimitation is imposed on R¹ and R². However, in view of readiness ofpost-treatment of reaction, it is preferred that R¹ and R² be botharylalkyl.

Specific examples of the above-mentioned acyl or divalent acyl groupseach formed of R¹ and R² linked to each other are formyl, acetyl,propionyl, 2-methylpropionyl, 2,2-dimethylpropionyl, benzoyl,p-methylbenzoyl, p-methoxybenzoyl, p-nitrobenzoyl, phenylacetyl,2-pyridylmethoxycarbonylvalyl, 3-pyridylmethoxycarbonylvalyl,4-pyridylmethoxycarbonylvalyl, 2-pyridylmethylaminocarbonylvalyl,6-methyl-2-pyridylmethylaminocarbonylvalyl,2-pyridylmethylaminocarbonylisoleucyl, phthaloyl, succinyl, maleoyl,etc. For convenience of processing after reaction and in view of pricesof reagents, the following groups are preferred: formyl, acetyl,propionyl, 2-methylpropionyl, 2,2-dimethylpropionyl, benzoyl,p-methylbenzoyl, p-methoxybenzoyl, p-nitrobenzoyl, phenylacetyl,phthaloyl, succinyl, and maleoyl. Illustrative examples of compoundsproviding these groups include 4-phenyl-3-formylamino-1-butene,4-phenyl-3-acetylamino-1-butene, 4-phenyl-3-propionylamino-1-butene,4-phenyl-3-(2'-methylpropionyl)amino-1-butene,4-phenyl-3-(2',2'-dimethylpropionyl)amino-1-butene,4-phenyl-3-benzoylamino-1-butene,4-phenyl-3-(p-methylbenzoyl)amino-1-butene,4-phenyl-3-(p-methoxybenzoyl)amino-1-butene,4-phenyl-3-(p-nitrobenzoyl)amino-1-butene,4-phenyl-3-phenylacetylamino-1-butene, 4-phenyl-3-phthalimido-1-butene,4-phenyl-3-succinimido-1-butene, and 4-phenyl-3-maleimido-1-butene.

Specific examples of the alkyloxycarbonyl group are methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl,isobutoxycarbonyl, and tert-butoxycarbonyl. For convenience ofprocessing after reaction and in view of prices of reagents, thefollowing groups are preferred: methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.Illustrative examples of compounds providing these groups include4-phenyl-3-methoxycarbonylamino-I-butene,4-phenyl-3-ethoxycarbonylamino-i-butene,4-phenyl-3-isopropoxycarbonylamino-1-butene,4-phenyl-3-isobutoxycarbonylamino-1-butene, and4-phenyl-3-tert-butoxycarbonylamino-1-butene.

Specific examples of the above-mentioned arylalkyloxycarbonyl groupinclude benzyloxycarbonyl, p-methylphenylmethoxycarbonyl,p-methoxyphenylmethoxycarbonyl, 2-pyridylmethoxycarbonyl,3-pyridylmethoxycarbonyl, 4-pyridylmethoxycarbonyl,1-(3'-pyridyl)ethoxycarbonyl, 2-thiazolylmethoxycarbonyl,4-thiazolylmethoxycarbonyl, 5-thiazolylmethoxycarbonyl,pyrazinylmethoxycarbonyl, 2-furanylmethoxycarbonyl, and3-furanylmethoxycarbonyl. For convenience of processing after reactionand in view of prices of reagents, the following groups are preferred:benzyloxycarbonyl, p-methylphenylmethoxycarbonyl, andp-methoxyphenylmethoxycarbonyl. Illustrative examples of compoundsproviding these groups include4-phenyl-3-benzyloxycarbonylamino-1-butene,4-phenyl-3-(p-methylphenylmethoxycarbonyl)amino-1-butene, and4-phenyl-3-(p-methoxyphenylmethoxycarbonyl)amino-1-butene.

Specific examples of the above-mentioned aryloxycarbonyl group arephenoxycarbonyl, p-methylphenoxycarbonyl, p-methoxyphenoxycarbonyl,p-nitrophenoxycarbonyl, 1-naphthyloxycarbonyl, and2-naphthyloxycarbonyl. For convenience of processing after reaction andin view of prices of reagents, the following groups are preferred:phenoxycarbonyl, p-methylphenoxycarbonyl, p-methoxyphenoxycarbonyl, andp-nitrophenoxycarbonyl. Illustrative compounds providing these groupsinclude 4-phenyl-3-phenoxycarbonylamino-1-butene,4-phenyl-3-(p-methylphenoxycarbonyl)amino-1-butene,4-phenyl-3-(p-methoxyphenoxycarbonyl)amino-1-butene, and4-phenyl-3-(p-nitrophenoxycarbonyl)amino-i-butene.

When R¹ and R² are both arylalkyl, examples of such arylalkyl groupsinclude benzyl, p-methylphenylmethyl, p-methoxyphenylmethyl, andp-nitrophenylmethyl. In view of readiness of post-treatment of reactionand costs of reagents, benzyl and p-methoxyphenylmethyl are preferred.Specifically, 4-phenyl-3-N,N-dibenzylamino-1-butene and4-phenyl-3-N,N-bis(p-methoxyphenylmethyl)amino-1-butene are mentioned.

The amount of phenylacetonitrile oxide or its precursors are generally0.2-50 times, preferably 1-20 times, and particularly preferably 1-5times, by mol, that of compound 4! or 5!.

The reaction is performed in the temperature range of -50° C. to as highas the boiling point of the solvent used in the reaction at the reactionpressure (up to approximately 200° C.), preferably between -20 and 120°C., and more preferably between -10 and 80° C. If the reactiontemperature is excessively low, reaction rate tends to retard, whereasif it is excessively high, selectivity of reaction tends to become poor.The reaction time is not particularly limited. It is generally between0.5 and 100 hours. The reaction pressure is not particularly limited,either. It is generally 0.1-50 atm, and preferably 1-50 atm.

No particular limitation is imposed on reaction solvents so far as theydo not affect the reaction. Examples of solvents used in the presentinvention include water, alcohols (e.g., methanol, ethanol, propanol,isopropyl alcohol, butanol, and tert-butyl alcohol), ethers (e.g.,diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran,dioxane, and 1,2-dimethoxyethane), nitrites (e.g., acetonitrile), esters(e.g., methyl acetate and ethyl acetate), hydrocarbons (e.g., hexane,heptane, benzene, toluene, and xylene), halogenated hydrocarbons (e.g.,methylene chloride, chloroform, 1,2-dichloroethane, and chlorobenzene),ketones (e.g., acetone and methyl ethyl ketone), carboxylic acids (e.g.,formic acid, acetic acid, and propionic acid), nitromethane, pyridine,dimethylsulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.These solvents are used singly or as a mixture. For convenience ofprocessing after reaction and in view of costs, it is preferred thatethers, hydrocarbons, or mixtures of one of ethers or hydrocarbons andwater be used. Particularly, hydrocarbons and mixtures of a hydrocarbonand water are preferred.

Purification methods after reaction may be ordinary ones (such asrecrystallization, chromatography, and distillation). Recrystallizationis particularly preferred in view that the operation is simple and thatthe production scale can be easily expanded. Among a number ofrecrystallization methods, a method which performs crystallization ofacid addition salts of 2-isoxazoline derivatives represented by formula1!, 2!, or 3! is effective, as it provides high purification efficiencyby permitting a reaction byproduct diphenylfuroxane to be removed withease. Moreover, high crystallization efficiency can be attained if acidaddition salts of the derivatives in which R¹ and R² of formula 1!, 2!,or 3! are both hydrogen atoms are recrystallized. Acid addition salts tobe submitted to a purification step may be arbitrarily selected fromsalts derived from inorganic acids or organic acids. They may be adductsresulting from addition of organic solvents or water.

Examples of acid addition salts derived from inorganic salts includehydrochlorides, hydrobromides, hydroiodides, sulfates, hydrogensulfates,phosphates, monohydrogenphosphates, dihydrogenphosphates, nitrates, andthiocyanates.

Examples of acid addition salts derived from organic acids includecarboxylic acids, sulfonic acids, and phosphonic acids. Examples of acidaddition salts derived from carboxylic acid include formates, acetates,propionates, butyrates, isobutyrates, cinnamates, benzoates,p-methylbenzoates, p-methoxybenzoates, p-nitrobenzoates, phenylacetates,lactates, oxalates, malonates, succinates, glutarates, adipates,maleates, fumarates, phthalates, terephthalates, citrates, malates,tartarates, salicylates, nicotinates, mandelates, and salts from aminoacids (such as glycine, alanine, aspartic acid, and glutamic acid).Examples of acid addition salts derived from sulfonic acid includemethanesulfonates, ethanesulfonates, benzenesulfonates,p-toluenesulfonates, p-chlorobenzenesulfonates,p-bromobenzenesulfonates, 2-naphthalenesulfonates, andcamphorsulfonates. Examples of acid addition salts derived fromphosphonic acid include methylphosphonates and phenylphosphonates.

The amount of acids used is usually 0.2-10 times, preferably 0.3-5times, and more preferably 0.4-2 times, by mol, that of 2-isoxazolinerepresented by formula 1!, 2!, or 3!.

When acid addition salts of(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline areobtained from acid addition salts of a mixture of (5RS,1'RS)- and(5RS,1'SR)-isomers or when acid addition salts of(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline areobtained from acid addition salts of a mixture of (5S,1'S)- and(5R,1'S)-isomers, use of hydrochlorides or p-toluenesulfonates ispreferred from the viewpoints of purification effects and costs.

Solvents for use in purification are not particularly limited so long asthey do not react with 2-isoxazoline derivatives represented by formula1!, 2!, or 3!, and acid addition salts of 2-isoxazoline derivativesrepresented by formula 1!, 2!, or 3! precipitate therefrom. Examples ofsuch solvents include water, alcohols (e.g., methanol, ethanol,propanol, isopropyl alcohol, butanol, and tert-butyl alcohol), ethers(e.g., diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran,dioxane, and 1,2-dimethoxyethane), nitrites (e.g., acetonitrile), esters(e.g., methyl acetate and ethyl acetate), hydrocarbons (e.g., hexane,heptane, benzene, toluene, and xylene), halogenated hydrocarbons (e.g.,methylene chloride, chloroform, 1,2-dichloroethane, and chlorobenzene),ketones (e.g., acetone and methyl ethyl ketone), carboxylic acids (e.g.,formic acid, acetic acid, and propionic acid), nitromethane, pyridine,dimethylsulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.These solvents are used singly or as a mixture. For convenience ofprocessing after reaction and in view of costs, it is preferred thatwater, alcohols, ethers, nitrites, esters, hydrocarbons, or mixtures ofthem be used. Acid addition salts which precipitated are subjected tofiltration and dried, if necessary, to obtain the desired acid additionsalts.

From the novel 2-isoxazoline derivatives of the present inventionrepresented by formula 1!, 2!, or 3! or from acid addition salts of thederivatives, 2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives can bederived. The latter derivatives can be used as intermediates in thesynthesis of medicines such as retrovirus protease inhibitors. In theprocess of preparing a(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivative, which isa significant compound among a number of2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives, optically active2-isoxazoline derivatives represented by formula 2! and their acidaddition salts are particularly important.

Several methods are feasible for preparing optically active2-isoxazoline derivatives represented by formula 2! or their acidaddition salts, including a method in which an optically active compoundrepresented by formula 5! is used as a starting material and a method inwhich the mixture of (5RS,1'RS)- and (5RS,1'SR)-isomers of 2-isoxazolinederivatives or their acid addition salts, or (5RS,1'RS)-2-isoxazolinederivatives or their acid addition salts are subjected to a proceduresuch as a optical resolution procedure for obtaining optically activecompounds. In a similar way, it is possible to obtain optically active2-isoxazoline derivatives represented by formula 3! or their acidaddition salts.

Among methods for obtaining optically active compounds by opticalresolution operation, there is a method described below in which anoptically active acid is used.

Although optically active acids are not particularly limited which maybe used in the reaction of a mixture of 2-isoxazoline derivatives offormulas 2! and 3! or a mixture of acid addition salts thereof and anoptically active acid for obtaining optically active acid addition saltsof 2-isoxazoline derivatives represented by formula 2!, optically activecarboxylic acid and optically active sulfonic acid are advantageouslyused. Specific examples of optically active carboxylic acids includelactic acid, tartaric acid, malic acid, mandelic acid, amino acids (suchas alanine, valine, aspartic acid, and glutamic acid), and theirderivatives. Examples of optically active sulfonic acids includecamphorsulfonic acid. From the viewpoints of purification efficiency andcosts, in order to obtain an acid addition salt of(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline, it ispreferred that (S)-mandelic acid be used as the optically active acid.On the other hand, in order for an acid addition salt of(5R,1'R)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline to beobtained, it is preferred that (R)-mandelic acid be used as theoptically active acid.

The amount of acids used is usually 0.2-10 times, preferably 0.3-5times, and more preferably 0.4-2 times, by mol, that of the2-isoxazoline derivative represented by formula 2! or 3!.

Solvents used on this occasion are not particularly limited so long asacid addition salts of 2-isoxazoline derivatives represented by formula2! or 3! precipitate therefrom. Examples of such solvents include water,alcohols (e.g., methanol, ethanol, propanol, isopropyl alcohol, butanol,and tert-butyl alcohol), ethers (e.g., diethyl ether, diisopropyl ether,dibutyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane),nitrites (e.g., acetonitrile), esters (e.g., methyl acetate and ethylacetate), hydrocarbons (e.g., hexane, heptane, benzene, toluene, andxylene), halogenated hydrocarbons (e.g., methylene chloride, chloroform,1,2-dichloroethane, and chlorobenzene), ketones (e.g., acetone andmethyl ethyl ketone), nitromethane, pyridine, dimethylsulfoxide.N,N-dimethylformamide, and N,N-dimethylacetamide. These solvents areused singly or as a mixture. For convenience of processing afterreaction and in view of costs, it is preferred that water, alcohols,ethers, nitrites, esters, hydrocarbons, or mixtures of them be used.Particularly, water, alcohols, hydrocarbons, and mixtures of them arepreferred.

When optically active acid addition salts which precipitated aresubjected to filtration and dried, if necessary, the desired opticallyactive acid addition salts can be obtained. By processing thethus-obtained optically active acid addition salts with an inorganicbase (such as NaOH and KOH) or an organic base (such as triethylamineand diisopropylethylamine), in other words, by neutralizing the acidwhich has been added, corresponding optically active 2-isoxazolinederivatives can be obtained.

The novel 2-isoxazoline derivatives represented by formula 1!, 2!, or 3!or acid addition salts of the derivatives can be converted to2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives which areintermediates in the synthesis of medicines such as retrovirus proteaseinhibitors by using a conventional method such as a method described byKurt B. G. Torssell ("Nitrile Oxides, Nitrones, and Nitronates inOrganic Synthesis" (VCH Publishers, Inc., New York, 1988)).

However, by reducing the novel 2-isoxazoline derivatives of formula 1!or 2! in accordance with the present invention,2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives represented byformula 6!, or (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexanederivatives represented by formula 7! and/or(2S,3S,5R)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivativesrepresented by formula 8!, can be synthesized advantageously in anindustrial scale. ##STR8## (wherein Ph represents phenyl; and each of R¹and R² independently represents hydrogen, acyl, alkyloxycarbonyl,arylalkyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylalkylaminocarbonyl, arylaminocarbonyl, alkyl, arylalkyl, aryl,alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, or R¹ and R² arelinked to each other to represent divalent acyl).

As described hereinabove, since the 2-isoxazoline derivative representedby formula 1! has two asymmetric carbons, one at the 5-position and theother at the 1'-position, the derivative has 4 types in total ofstereoisomers. Similarly, since a2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivative represented byformula 6! has three asymmetric carbons, one at each of the 2-, 3-, and5-positions, the derivative has 8 types in total of stereoisomers.Unless otherwise indicated, it must be understood that each derivativeencompasses these four or eight stereoisomers and a mixture of them inan arbitrary ratio. In connection to this, if, for example, a(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinederivative represented by formula 2! is used as a starting material,either one or both of a(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivative and a(2S,3S,5R)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivativerepresented by formulas 7! and 8!, respectively, can be obtained in anarbitrary ratio, because the 5- and 1'-positions of the compound offormula 1! correspond to 3- and 2-positions of a2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivative, respectively, andtheir stereochemical characters are normally kept unchanged during theconversion of a 2-isoxazoline derivative of formula 1! to a compound offormula 6!.

Reducing methods for the 2-isoxazoline derivatives are not particularlylimited. For example, there are a method in which hydrogen or compoundsserving as hydrogen sources (for example, formic acid, etc.) are used toperform catalytic hydrogenation in the presence of a metallic catalystand a method which uses, as reducing agents, metals (for example,sodium, zinc, etc.), metal hydrides (for example, lithium aluminumhydride, sodium borohydride, sodium aluminum bis(methoxyethoxy) hydride,aluminum diisobutyl hydride, etc.). In view of selectivity of reaction,operability, safety, etc., reduction using catalytic hydrogenation andreduction using metal hydrides as reducing agents are preferred.Particularly, reduction using catalytic hydrogenation is more preferred.

2-Isoxazoline derivatives represented by formula 1! or 2! which are usedfor reduction are not particularly limited so long as side reactions inreducing methods to be used are practically negligible.

In catalytic hydrogenation reduction using hydrogen, it is preferredthat at least one of R¹ and R² of formula 1! or 2! be an electronattractive group, or that R¹ and R² are both groups other than hydrogen.In cases where at least one of R¹ or R² is an electron attractive group,preferable electron attractive groups R¹ and R² are, for example, acyl,alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl,alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, or those which linkto each other to form a divalent acyl group. For convenience ofselectivity of reaction and processing after reaction, preferable groupsare acyl, alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl, anddivalent acyl formed of R¹ and R² linked to each other. Of these, acyl,alkyloxycarbonyl, aryloxycarbonyl, and a divalent acyl formed of R¹ andR² linked to each other are more preferred, and alkyloxycarbonyl isparticularly preferred.

If both R¹ and R² are the other groups than hydrogen, no particularlimitation is imposed on R¹ and R². However, in view of readiness ofpost-treatment of reaction, it is preferred that R¹ and R² be botharylalkyl.

Specific examples of the above-mentioned acyl or divalent acyl groupformed of R¹ and R² linked to each other are formyl, acetyl, propionyl,2-methylpropionyl, 2,2-dimethylpropionyl, benzoyl, p-methylbenzoyl,p-methoxybenzoyl, p-nitrobenzoyl, phenylacetyl,2-pyridylmethoxycarbonylvalyl, 3-pyridylmethoxycarbonylvalyl,4-pyridylmethoxycarbonylvalyl, 2-pyridylmethylaminocarbonylvalyl,6-methyl-2-pyridylmethylaminocarbonylvalyl,2-pyridylmethylaminocarbonylisoleucyl, phthaloyl, succinyl, maleoyl,etc. For convenience of processing after reaction and in view of pricesof reagents, the following groups are preferred: formyl, acetyl,propionyl, 2-methylpropionyl. 2,2-dimethylpropionyl, benzoyl,p-methylbenzoyl, p-methoxybenzoyl, p-nitrobenzoyl, phenylacetyl,phthaloyl, succinyl, and maleoyl.

Specific examples of the above-mentioned alkyloxycarbonyl group includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,sec-butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl. Forconvenience of processing after reaction and in view of prices ofreagents, the following groups are preferred: methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, andtert-butoxycarbonyl.

Specific examples of the above-mentioned aryloxycarbonyl group arephenoxycarbonyl, p-methylphenoxycarbonyl, p-methoxyphenoxycarbonyl,p-nitrophenoxycarbonyl, 1-naphthyloxycarbonyl, and2-naphthyloxycarbonyl. For convenience of processing after reaction andin view of prices of reagents, the following groups are preferred:phenoxycarbonyl, p-methylphenoxycarbonyl, p-methoxyphenoxycarbonyl, andp-nitrophenoxycarbonyl.

When R¹ and R² are both arylalkyl groups, examples of such arylalkylgroups include benzyl, p-methylphenylmethyl, p-methoxyphenylmethyl, andp-nitrophenylmethyl. In view of readiness of post-treatment of reactionand costs of reagents, benzyl is preferred.

In a reduction process using metal hydrides as reducing agents, it ispreferred that each of R¹ and R² be independently hydrogen, alkyl,arylalkyl, aryl, acyl, alkyloxycarbonyl, arylalkyloxycarbonyl, oraryloxycarbonyl since a side reaction is negligible. For convenience ofselectivity of reaction and processing after reaction, hydrogen, alkyl,arylalkyl, and aryl are more preferred. Specific examples of an alkylgroup include methyl, ethyl, propyl, and isopropyl. Specific examples ofan arylalkyl group include benzyl, p-methylphenylmethyl,p-methoxyphenylmethyl, and p-nitrophenylmethyl. Specific examples of anaryl group include phenyl, p-methylphenyl, p-methoxyphenyl, andp-nitrophenyl.

When catalytic hydrogenation reduction is performed, homogeneous orheterogeneous metallic catalysts which are conventionally used may beused. In view of operability, heterogeneous catalysts are preferred.Metals usable as catalysts are, for example, precious metal catalysts,such as palladium, platinum, ruthenium, and rhodium, and Raney nickel.In view of selectivity of reaction and prices of catalysts, palladiumand platinum catalysts are preferred. These palladium and platinumcatalysts, however, are not particularly limited and may be the metalelements or the metallic compounds, or may be supported on arbitrarycarriers (for example, active carbon, Al₂ O₃, CaCO₃, BaCO₃, BaSO₄,MgCO₃, SiO₂ ' and diatomaceous earth). The amount of a catalytic metalto be supported on a carrier is not particularly limited. It is usually0.1-10%, preferably 0.5-25%, more preferably 1-10%. Also, mixtures ofdifferent catalysts may be used.

The amount of a catalyst is not particularly limited. The weight ratioof a catalyst to a reactive substrate is usually 0.01-100%, preferably0.1-50%, and more preferably 0.1-25%.

In catalytic hydrogenation reduction, a side reaction may occur in whichan amino group formed by the reduction reacts with an imine compound,which is present as a reaction intermediate, formed by the cleavage of aN--O bond of an isoxazoline ring, and, as the result, a secondary amineand a tertiary amine are formed. Under normal reaction conditions, thereaction rate may be slow in some case, so that a large amount (forexample, 50-100% of a weight ratio to substrate) of metallic catalyst isrequired to complete the reaction. To suppress such a side reactionand/or to increase a reaction rate (or to reduce the amount of ametallic catalyst used), it is effective to add an ammonia source, acidor a base to a reaction system singly or in the form of a mixture(including salts formed of acid and base) thereof. Ammonia sources are,for example, ammonia gas and aqueous ammonia and ammonium salts such asammonium acetate, ammonium chloride, ammonium carbonate, ammoniumhydrogencarbonate, ammonium sulfate, ammonium hydrogensulfate,monoammonium dihydrogenphosphate, diammonium monohydrogenphosphate, andtriammonium phosphate. Preferably, ammonium gas, aqueous ammonia, andammonium acetate are used. Acids to be used include inorganic acids andcarboxylic acid. Inorganic acids to be used are, for example, hydrogenchloride gas, hydrochloric acid, hydrobromic acid, hydriodic acid,sulfuric acid, phosphoric acid, nitric acid, thiocyanic acid, and boricacid. Preferably, hydrogen chloride gas, boric acid are used. Carboxylicacids are, for example, formic acid, acetic acid, propionic acid,butyric acid, isobutyric acid, cinnamic acid, benzoic acid,p-methylbenzoic acid, p-methoxybenzoic acid, p-nitrobenzoic acid, phenylacetic acid, lactic acid, oxalic acid, malonic acid, succinic acid,glutaric acid, adipic acid, maleic acid, fumaric acid, phthalic acid,terephthalic acid, citric acid, malic acid, tartaric acid, salicylicacid, nicotinic acid, mandelic acid, amino acids (such as glycine,alanine, aspartic acid, and glutamic acid). Preferably, formic acid,acetic acid, propionic acid, benzoic acid, and oxalic acid are used.Bases are, for example, ammonia, triethylamine, N-methylmorpholine,sodium methoxide, sodium ethoxide, potassium t-butoxide, sodiumhydroxide, potassium hydroxide, sodium carbonate, and potassiumcarbonate. Preferably, ammonia, sodium methoxide, sodium ethoxide,potassium t-butoxide, sodium hydroxide, and potassium hydroxide areused.

The amount of additives to be incorporated to these reacting systems isnot particularly limited, and it is usually 0.01-100 times, andpreferably 0.1-50 times, by mol, that of a reactive substrate.

In catalytic hydrogenation reduction, the amount of hydrogen used isusually 0.5-100 times, preferably 1-50 times, and more preferably 1-10times by mol as much as that of3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline derivativesrepresented by formula 1! or 2!.

In reduction using metal hydrides as reducing agents, the amount ofmetal hydrides, such as lithium aluminum hydride, sodium borohydride,sodium aluminum bis(methoxyethoxy) hydride, aluminum diisobutyl hydride,is usually 0.1-10 times, preferably 0.5-5 times, and more preferably0.8-2 times, by mol, that of3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline derivativesrepresented by formula 1! or 2!.

Solvents used for reaction are not particularly limited as long as theydo not affect the reaction in any reduction method. Examples of suchsolvents include water, alcohols (e.g., methanol, ethanol, propanol,isopropyl alcohol, butanol, and tert-butyl alcohol), ethers (e.g.,diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran,dioxane, and 1,2-dimethoxyethane), nitriles (e.g., acetonitrile), esters(e.g., methyl acetate and ethyl acetate), hydrocarbons (e.g., hexane,heptane, benzene, toluene, and xylene), halogenated hydrocarbons (e.g.,methylene chloride, chloroform, 1,2-dichloroethane, and chlorobenzene),ketones (e.g., acetone and methyl ethyl ketone), carboxylic acids (e.g.,formic acid, acetic acid, and propionic acid), nitromethane, pyridine,dimethylsulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.These solvents are used singly or as a mixture. The amount of a solventis not particularly limited. The amount of a solvent used is usually0.1-1000 times, preferably 0.1-100 times that of a reactive substrate.

In catalytic hydrogenation reduction, it is preferred that water,alcohols, ethers, esters, hydrocarbons, and carboxylic acids are usedsingly or in the form of a mixture thereof in order to suppress sidereactions. More preferably, alcohols and carboxylic acids are usedsingly or in the form of a mixture thereof. As described before, anammonium source, acid, or base may be added to the solvents.

In a reduction process using metal hydrides as reducing agents, it ispreferred that ethers and hydrocarbons be used singly or in the form ofa mixture thereof in order to suppress side reactions. Ethers areparticularly preferred.

In any manner of reduction, reaction is performed usually at atemperature ranging from -80° C. to near a boiling point (about 200° C.)of a solvent, preferably at -50 to 120° C., more preferably at -20 to80° C. When a reaction temperature is too low, a reaction rate tends todecrease. When a reaction temperature is too high, selectivity ofreaction tends to become poor. The reaction time is not particularlylimited, and it is usually 0.5-100 hours.

The reaction pressure is not particularly limited in any reductionmethod. It is usually 0.01-150 atm, and is preferably 1-50 atm.

In order to obtain (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexanederivatives, which are important intermediates in the synthesis ofmedicines such as retrovirus protease inhibitors, when(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinederivatives represented by formula 2! are used as substrates forreduction, a product of reaction is usually obtained as a mixture of(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives,(2S,3S,5R)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives, otherbyproducts, and materials not reacted. The ratio of production between(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives and(2S,3S,5R)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives dependson the structure of R¹ and R² of(5S,1'S)-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinederivatives represented by formula 2!, reducing methods, and conditionsof reaction. For example, when catalytic hydrogenation is performed withR¹ being hydrogen and R² being a tert-butoxycarbonyl group,(2S,3S,5S)-5-amino-2-tert-butoxycarbonylamino-1,6-diphenyl-3-hydroxyhexaneand(2S,3S,5R)-5-amino-2-tert-butoxycarbonylamino-1,6-diphenyl-3-hydroxyhexaneare produced in a ratio of about 3:1 to 20:1.

After reaction, separation from byproducts and unreacted materialsand/or separation of stereoisomers can be performed by ordinarypurification methods, for example, recrystallization, chromatography,and distillation. Of these, purification by recrystallization ispreferable because of simple operation and easy scaleup. Ofrecrystallizing methods, crystallization as acid addition salts ispreferred because of highly effective separation of stereoisomers andremoval of byproducts. Acid addition salts for use in purificationprocesses are arbitrarily selectable from salts derived from inorganicor organic acids. These acid addition salts may be adducts of organicsolvents and water.

Examples of acid addition salts derived from an organic acid includehydrochlorides, hydrobromides, hydroiodides, sulfates, hydrogensulfates,phosphates, monohydrogenphosphates, dihydrogenphosphates, nitrates, andthiocyanates.

Examples of acid addition salts derived from organic acids includecarboxylic acids, sulfonic acids, and phosphonic acids. Examples of acidaddition salts derived from carboxylic acid include formates, acetates,propionates, butyrates, isobutyrates, cinnamates, benzoates,p-methylbenzoates, p-methoxybenzoates, p-nitrobenzoates, phenylacetates,lactates, oxalates, malonates, succinates, glutarates, adipates,maleates, fumarates, phthalates, terephthalates, citrates, malates,tartarates, salicylates, nicotinates, mandelates, and salts from aminoacids (such as glycine, alanine, aspartic acid, and glutamic acid).Examples of acid addition salts derived from sulfonic acid include, forexample, methanesulfonates, ethanesulfonates, benzenesulfonates,p-toluenesulfonates, p-chlorobenzenesulfonates,p-bromobenzenesulfonates, 2-naphthalenesulfonates, andcamphorsulfonates. Examples of acid addition salts derived fromphosphonic acid include methylphosphonates and phenylphosphonates.

The amount of acids used is usually 0.2-10 times, preferably 0.3-5times, and more preferably 0.4-2 times by mole as much as that of2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivative represented byformula 6!, 7!, or 8!. Solvents for use in purification are notparticularly limited so long as they do not react with2.5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives represented byformula 6!, 7!, or 8! and their acid addition salts. Examples of suchsolvents include water, alcohols (e.g., methanol, ethanol, propanol,isopropyl alcohol, butanol, and tert-butyl alcohol), ethers (e.g.,diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran,dioxane, and 1,2-dimethoxyethane), nitriles (e.g., acetonitrile), esters(e.g., methyl acetate and ethyl acetate), hydrocarbons (e.g., hexane,heptane, benzene, toluene, and xylene), halogenated hydrocarbons (e.g.,methylene chloride, chloroform, 1,2-dichloroethane, and chlorobenzene),ketones (e.g., acetone and methyl ethyl ketone), carboxylic acids (e.g.,formic acid, acetic acid, and propionic acid), nitromethane, pyridine,dimethylsulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.These solvents are used singly or as a mixture. Of these, it ispreferred that water, alcohols, ethers, esters, and hydrocarbons areused singly or as a mixture of them. The amount of solvent forrecrystallization is not particularly limited. It is usually 0.1-1,000times, preferably 0.5-200 times that of a reactive substrate.

When a 2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivative representedby formula 7! and/or formula 8! is produced by reducing a(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinederivative represented by formula 2!, it is usually obtained in the formof a mixture of stereoisomers at the 5-position. Accordingly, in orderto obtain the respective isomers at high purities, purification mustinvolve separation of the stereoisomers. Particularly, purification of(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives, whichare particularly significant intermediates in the synthesis of medicinessuch as retrovirus protease inhibitors and represented by formula 7!, orof their acid addition salts is important (the purification includesseparation and purification of a(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivativerepresented by formula 7! from a mixture of this derivative and a(2S,3S,5R)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivativerepresented by formula 8!).

When purification is performed for the above purposes, a mixture isadvantageously purified by recrystallizing the mixture in the form of anacid addition salt. Among recrystallization protocols, an advantageouspurification method is recrystallization of acid addition salts of2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives represented byformulas 7! and 8! in which at least one of R¹ or R² is acyl,alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl,alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, or R¹ and R² arelinked to each other to form divalent acyl, and the amino group at the2-position is protected by an electron attractive group, in view of easyremoval of byproducts and unreacted products and easy separation ofstereoisomers. Specifically, it is particularly preferred thatcarboxylic acid adducts of(2S,3S,5S)-5-amino-2-tert-butoxycarbonylamino-1,6-diphenyl-3-hydroxyhexanederivatives be selectively taken by recrystallization from a mixture ofacid addition salts formed of(2S,3S,5S)-5-amino-2-tert-butoxycarbonylamino-1,6-diphenyl-3-hydroxyhexane,(2S,3S,5R)-5-amino-2-tert-butoxycarbonylamino-1,6-diphenyl-3-hydroxyhexane,and a carboxylic acid. As regards the carboxylic acid, oxalic acid isparticularly preferred. By this purification method, it is possible toobtain(2S,3S,5S)-5-amino-2-tert-butoxycarbonylamino-1,6-diphenyl-3-hydroxyhexaneor its acid addition salts with a high purity.

When the thus-obtained 2,5-diamino-1,6-diphenyl-3-hydroxyhexanederivative has a substituent serving as a protective group for amino atthe 2-position, the derivative can be converted to2,5-diamino-1,6-diphenyl-3-hydroxyhexane by suitably eliminating theprotection of amino group. Also, if the derivative has a substituentserving as a protective group for the 2-position amino group duringreduction, the newly produced free amino group at the 5-position by thereduction and another amino group at the 2-position are alreadydiscriminated, and thus, such a derivative is very useful for modifyingthese two amino groups differently from each other in the synthesis ofmedicines.

The present invention will next be described in detail by way ofexamples, which should not be construed as limiting the invention.

EXAMPLE 1

(A) Phenylacetohydroximoyl chloride

Phenylacetaldehyde oxime (45.96 g, 340 mmol) was dissolved inN,N-dimethylformamide (100 ml). N-chlorosuccinimido (45.41 g, 340 mmol)was added to the solution in 10 parts (4.54 g, 34 mmol each) atintervals of 20 minutes. During the addition, the temperature of thereaction mixture was maintained within a temperature range between 11and 18° C. in a water bath. After completion of addition, the mixturewas stirred for further 3 hours while maintaining the temperaturebetween 15 and 17° C. Ice-water (200 ml) and toluene (200 ml) were addedto the reaction mixture for extraction. The aqueous layer was furtherextracted with toluene (100 ml). Organic layers were combined and washedwith water (250 ml) three times, then dried over anhydrous magnesiumsulfate. The desiccant was filtered off, and the filtrate was used inthe next step without concentration.

(B) (5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate

(S)-3-tert-Butoxycarbonylamino-4-phenyl-1-butene (42.05 g, 170 mmol) andtriethylamine (41.29 g, 408 mmol) were dissolved in toluene (62 ml). Tothe resulting solution phenylacetohydroximoyl chloride (prepared from340 mmol of phenylacetaldehyde oxime) prepared in Example 1 (A) intoluene was added dropwise at room temperature over 8 hours. The mixturewas stirred overnight at room temperature. Water (500 ml) was then addedto the mixture, followed by extraction with toluene. The extract wascondensed under reduced pressure to give an orange liquid (86.62 g),containing(5S,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolineand(5R,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline.Reversed phase HPLC revealed that the ratio of(5S,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylmethyl)-2-isoxazolineto(5R,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolinewas 7:3. The liquid was dissolved in ethanol (200 ml), p-toluenesulfonicacid monohydrate (38.81 g, 204 mmol) was added. The resulting solutionwas refluxed with heat for 1.5 hours, to give a brown solutioncontaining(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate and(5R,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate. Ethyl acetate (400 ml) was added to the solution,and the mixture was cooled. Precipitated crystals were separated byfiltration under reduced pressure and washed with ethanol/ethyl acetate(1/10) and ethyl acetate. The obtained wet crystals were recrystallizedtwice from ethanol/ethyl acetate (1/2) to give the desired compound ascolorless crystals. Yield: 40.43 9 (52.5%). m.p. 206.5-208.5° C.(decomposed).

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7 70(d,2H,J=8.2Hz), 7.33-7.18(m, 12H),4.53(dt, 1H,.J=7.6 Hz), 3.66(d, 1H, J=15.0 Hz), 3.64(d, 1H, J=15.0 Hz),3.44(broad q, 1H, J=7.3 Hz), 2.94(dd, 1H, J=17.7, 10.5 Hz), 2.90(m, 2H),2.62(dd, 1H, J=17.7, 7.5 Hz), 2.35(s, 3H). IR(KBr, cm⁻¹)3028, 2938,1621, 1531, 1493, 1209, 1177, 1011, 704, 568. α!_(D) ²⁵ +77° (c=1.1, CH₃OH). Mass spectra (FD):m/z 281(M^(+-TsO)).

Anal. Calcd. for the adduct C₂₅ H₂₈ N₂ O₄ S.0.4CH₃ COOC₂ H₅ : C,65.49;H, 6.45; N, 5.74%. Found: C, 65.66; H,6.31; N, 5.49%.

EXAMPLE 2

(A) (S)-3-Phthalimido-4-phenyl-1-butene

(S)-3-Amino-4-phenyl-1-butene (3.0 g. 20.4 mmol) was dissolved intetrahydrofuran (20 ml). To the solution, an aqueous solution (10 ml) ofN-carboethoxyphthalimido (4.9 g, 22.4 mmol) and anhydrous sodiumcarbonate (2.38 g, 22.4 mmol) were added and stirred at room temperaturefor 1.5 hours. The reaction mixture was concentrated under reducedpressure to remove tetrahydrofuran, followed by extraction withdiisopropyl ether. The organic layer was washed successively with 1Mhydrochloric acid, saturated aqueous sodium bicarbonate, and saturatedbrine and dried over anhydrous magnesium sulfate. After the desiccantwas filtered off, the filtrate was concentrated under reduced pressureto give the desired compound as pale yellow crystals. Yield: 5.56 g.

¹ H NMR(500 MHz,CDCl₃) δ ppm 7.75(m,2H), 7.65(m, 2H), 7.19-7.11(m, 5H),6.27(ddd, 1H, J=17.2, 10.3, 7.2 Hz), 5.22(d, 1H, J=17.2 Hz), 5.19(d, 1H,J=10.3 Hz), 5.05(ddd, 1H), 3.42(dd, 1H, J=13.8, 8.99 Hz), 3.21(d, 1H,J=13.8, 6.5 Hz).

(B) Phenylacetohydroximoyl chloride

Phenylacetaldehyde oxime (33.80 g, 250 mmol) was dissolved inN,N-dimethylformamide (90 ml) and cooled in ice bath. To the solution,N-chlorosuccinimido (33.39 g, 250 mmol) was added. After completion ofaddition, the reaction mixture was stirred for 4 hours while graduallyraising the temperature to room temperature. Ice-water (150 ml) anddiisopropyl ether (200 ml) were added to the reaction mixture forextraction. The aqueous layer was further extracted with diisopropylether (100 ml). Organic layers were combined and washed with water threetimes, followed by drying over anhydrous magnesium sulfate. Thedesiccant was filtered off, and the filtrate was concentrated underreduced pressure to give the desired compound as a khaki solid. Thesolid was used in the next step without purification. Yield: 40.2 9(98%)

(C) (5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate

(S)-3-Phthalimido-4-phenyl-1-butene (3.0 g, 10.8 mmol) prepared inExample 2 (A) was dissolved in toluene (10 ml). To the solution, anaqueous solution (20 ml) of sodium carbonate (3.15 9, 30 mmol) wasadded. Phenylacetohydroximoyl chloride (4.59 g, 27.0 mmol) prepared inExample 2 (B) and dissolved in toluene (60 ml) was added dropwise atroom temperature over 5 hours. After stirring at room temperature for 15hours, water was added to the solution for separation. The organic layerwas washed with water and dried over anhydrous sodium sulfate. After thedesiccant was filtered off, the filtrate was concentrated under reducedpressure to give an oil containing(5S,1'S)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazolineand(5R,1'S)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazoline.Reversed phase HPLC revealed that the ratio of(5S,1'S)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazolineto(5R,1'S)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazolinewas 6:4. The oil was dissolved in methanol (10 ml). An aqueousmethylamine solution (40%, 15 ml) was added and stirred at 60° C. for 4hours. The reaction mixture was concentrated under reduced pressure, andthe residue was added with water and toluene for liquid separation. Theseparated organic layer was washed with water and dried over anhydroussodium sulfate. After the desiccant was filtered off, the filtrate wasconcentrated under reduced pressure, to give an oil containing(5S.1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline and(5R, 1'S)-3-phenylmethyl-5-(1-amino-2'-phenylethyl)-2-isoxazoline. Theoil was dissolved in ethanol (20 ml). p-Toluenesulfonic acid monohydrate(2.06 g, 10.8 mmol) was added to the solution and refluxed with heat togive a brown solution containing(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate and(5R,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate. To the solution, ethyl acetate (40 ml) was added,and the mixture was cooled to precipitate crystals. The crystals werecollected by filtration and washed with ethanol/ethyl acetate (1/10) andthen with ethyl acetate. Crude crystals were recrystallized from ethanol(20 ml) and ethyl acetate (40 ml) to give the desired compound ascolorless crystals. Yield: 1.76 g (36%).

The obtained compound agreed with the compound obtained in Example 1(B).

EXAMPLE 3

(A) (S)-3-Formylamino-4-phenyl-1-butene

(S)-3-Amino-4-phenyl-1-butene (5.2 g, 35.4 mmol) was dissolved in ethylformate (100 ml) and the solution was refluxed with heat for 6 hours.After completion of reaction, the solution was concentrated underreduced pressure to give the desired compound as an orange oil. Yield:6.44 g.

¹ H NMR(500 MHz, CDCl₃) δ ppm 8.16(broad s, 1H), 7.33-7.1 6(m, 5H),5.83(ddd, 1H, J=15.8, 10.3, 5.4 Hz), 5.47(broad s, 1H), 5.15-5.12(m,2H), 4. 88(m, 1H), 2. 90(m, 2H), In addition, a rotational isomer withrespect to the amide bond of N-formyl group was observed as indicatedbelow (proportion to the former: about 3/1), δ ppm 7.84(d, 1H, J=112Hz), 7.33-7.16(m, 5H), 5.91 (ddd, 1H), 5.55(broad s, 1H), 5.20-5.15(m,2H), 4.20(m, 1H), 2.97-2.74(m, 2H).

(B) (5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate

(S)-3-formylamino-4-phenyl-1-butene (3.0 g, 17.1 mmol) prepared inExample 3 (A) was dissolved in toluene (10 ml). To the solution,triethylamine (3.46 g, 34.2 mmol) was added. A toluene solution (60 ml)of phenylacetohydroximoyl chloride prepared in a manner similar to thatdescribed in Example 1 (A) from phenylacetaldehyde oxime (4.63 g, 34.2mmol) was added dropwise at room temperature over 4 hours. Afterstirring the mixture at room temperature for 15 hours, water was addedfor liquid separation. The separated organic layer was washed with waterand dried over anhydrous sodium sulfate. After the desiccant wasfiltered off, the filtrate was concentrated under reduced pressure togive an oil containing(5S,1'S)-3-phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazolineand(5R,1'S)-3-phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazoline.Reversed phase HPLC revealed that the ratio of(5S,1'S)-3-phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazolineto(5R,1'S)-3-phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazolinewas 6:4. The oil was dissolved in ethanol (25 ml). p-Toluenesulfonicacid monohydrate (4.48 g, 23.5 mmol) was added to the solution andrefluxed with heat for 4 hours to give a brown solution containing(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate and(5R,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate. Ethyl acetate (50 ml) was added to the solution andthe mixture was cooled to precipitate crystals. The crystals werecollected by filtration and washed with ethanol/ethyl acetate (1/10) andthen with ethyl acetate. Crude crystals were recrystallized from ethanol(25 ml) and ethyl acetate (50 ml) to give the desired compound ascolorless crystals. Yield: 2.34 g (30%).

The obtained compound agreed with the compound obtained in Example 1(B).

EXAMPLE 4

(A) (S)-3-N,N-Dibenzylamino-4-phenyl-1-butene and(S)-3-N,N-dibenzylamino-4-phenyl-1-butene hydrochloride

Potassium carbonate (95.3 g, 690 mmol), water (143 g), and benzylchloride (81.1 g, 641 mmol) were added to (S)-3-amino-4-phenyl-1-butene(34.3 g, 233 mmol). The mixture was stirred at 80° C. for 48 hours.Toluene (622 g) and water (143 g) were added to the reaction mixture,and the separated organic layer was washed with water (143 g). Reversedphase HPLC revealed that the toluene solution contained 52.2 9 (160mmol, yield 69%) of the desired compound. The solution was concentratedunder reduced pressure to give the desired compound as a yellow oil.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.23(m,13H), 7. 04(m,2H), 5.87(ddd, 1H,J=17.3, 10.3, 8.0 Hz), 5.24(d, 1H, J=10.3 Hz), 5.02(d, 1H, J=17.2 Hz),3.82(d, 2H, J=13.9 Hz), 3.45(d, 2H, J=14.0 Hz), 3.38(q, 1H, J=7.7 Hz),3.02(dd, 1H, J=13.8, 7.7 Hz), 2.78(dd, 1H, J=13.8, 7.5 Hz). IR(neat,cm⁻¹)3161, 3025, 2800, 1494, 1454, 1119, 1073, 1028, 978, 923, 742, 697.

An oil (16.37 g) containing (S)-3-N,N-dibenzylamino-4-phenyl-1-buteneobtained in a manner similar to that described above was dissolved in asolvent mixture of isopropyl alcohol (20 ml) and diisopropyl ether (50ml), and was further combined with conc. hydrochloric acid (7.60 g). Theresulting mixture was heated to 70° C. while stirring, and then cooledto room temperature, followed by cooling to 0° C. with ice. A colorlesssolid precipitated was collected by filtration and washed with a mixtureof isopropyl alcohol (10 ml) and diisopropyl ether (25 ml) and thenwashed twice with diisopropyl ether (20 ml). The obtained wet crystalswere dried under reduced pressure at room temperature to give colorlesscrystals. Yield: 11.62 g. m.p. 139.1-141.1° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.80(m, 4H), 7.40(m,6H), 7.19(m, 3H),7.12(m, 2H), 5.98(dt, 1H, J=17.0, 9.8 Hz), 5.51(d, 1H, J=10.4 Hz),4.99(d, 1H, J=17.2 Hz), 4.64(dd, 1H, J=13.3, 4.6 Hz), 4.19(m, 2H),4.06(m, 2H), 3.98(broad t, 1H, J=10.3 Hz), 2.83(t, 1H, J=12.0 Hz).IR(KBr, cm⁻¹)3466, 2488, 1459, 935, 749, 738, 699, 498.

(B) Phenylacetohydroximoyl chloride

Phenylacetaldehyde oxime (40.5 g, 300 mmol) was dissolved inacetonitrile (100 ml). To the solution, a 6.7% aqueous hydrochloric acid(145 g) and then an 8.5% aqueous sodium hypochlorite (262 g, 299 mmol)were added dropwise at -10° C. over 2.3 hours. The mixture was stirredat -5° C. for 30 minutes and then combined with toluene (200 ml) forextraction. The separated organic layer was washed twice with water (200ml). Reversed phase HPLC revealed that the extract contained 40.3 g (238mmol, yield 79%) of the desired compound. The solution was used in thenext step without concentration.

(C)(5S,1'S)-3-Phenylmethyl-5-(1'-N,N-dibenzylamino-2'-phenylethyl)-2-isoxazoline

A 10% aqueous sodium carbonate (124 g, 117 mmol) was added to an oil(34.3 g) containing (S)-3-N,N-dibenzylamino-4-phenyl-1-butene (21.88 g,66.9 mmol) prepared in Example 4 (A). A toluene solution (159.7 g)containing phenylacetohydroximoyl chloride (24.95 g, 147 mmol) preparedin Example 4 (B) was added to the mixture dropwise at room temperatureover 7.5 hours. After stirring the mixture at room temperature for 14.5hours, water was added, separated, followed by washing the organic layerwith water. The organic layer was concentrated under reduced pressure togive an oil (61.4 g) containing(5S,1'S)-3-phenylmethyl-5-(1'-N,N-dibenzylamino-2'-phenylethyl)-2-isoxazolineand(5R,1'S)-3-phenylmethyl-5-(1'-N,N-dibenzylamino-2'-phenylethyl)-2-isoxazoline.The oil (60.3 g) was dissolved in isopropyl alcohol (92.4 g) andcombined with conc. hydrochloric acid (8.0 g) and water (30.8 g). Theresulting mixture was stirred at room temperature for 1 hour and furtherwhile cooling with ice for 1 hour. The precipitated crystals werecollected by filtration under reduced pressure and washed with isopropylalcohol (23.1 g). The crystals were dried under reduced pressure to givethe desired compound as colorless crystals. Yield: 3.39 g (25%).

The obtained compound agreed with the compound obtained in Example 21.

EXAMPLE 5

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate

(RS)-3-tert-Butoxycarbonylamino-4-phenyl-1-butene (6.4 g, 25.9 mmol) wasdissolved in toluene (10 ml), and was added triethylamine (5.50 g, 54.3mmol). To the solution, a toluene solution (100 ml) ofphenylacetohydroximoyl chloride prepared in a manner similar to thatdescribed in Example 1 (A) was added dropwise to the mixture at roomtemperature over 6 hours. After stirring at room temperature for 15hours, water was added to the solution for liquid separation. Theorganic layer was washed and dried over anhydrous sodium sulfate. Afterthe desiccant was filtered off, the filtrate was concentrated underreduced pressure to give an oil containing(5RS,1'RS)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolineand(5RS,1'SR)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline.Reversed phase HPLC revealed that the ratio of(5RS1'RS)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolineto(5RS,1'SR)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolinewas 7:3. The oil was dissolved in ethanol (55 ml), and p-toluenesulfonicacid monohydrate (5.5 g, 28.9 mmol) was added and the solution wasrefluxed with heat for 2 hours. The reaction mixture was concentratedunder reduced pressure, dissolved in ethanol (30 ml) again, and thenrefluxed with heat to give a brown solution containing(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate and(5RS,1'SR)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate. Ethyl acetate (150 ml) was added, and the mixturewas cooled to precipitate crystals. The precipitated crystals werecollected by filtration and washed with ethanol/ethyl acetate (1/10) andfurther with ethyl acetate. Crude crystals were recrystallized fromethanol (30 ml) and ethyl acetate (120 ml) to give the desired compoundas colorless crystals. Yield: 4.13 g (35%). m.p. 198.5-200.7° C.(decomposed).

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7.70(d.2H, J=8.2 Hz), 7.33-7.18(m, 12H),4.53(dt, 1H, J=7.6 Hz), 3.66(d, 1H, J=15.0 Hz), 3.64(d, 1H, J=15.0 Hz).3.44(broad q, J=7.3 Hz), 2.94(dd, 1H, J=17.7, 10.5 Hz), 2.90(m, 2H),2.62(dd, 1H, J=17.7, 7.5 Hz), 2.35(s, 3H). IR(KBr, cm⁻¹)3028, 2940,1620, 1531, 1494, 1209, 1177, 1034, 1011, 704, 682.569. Anal. Calcd. forthe adduct C₂₅ H₂₈ N₂ O₄ S.0.3CH₃ COOC₂ H₅ : C, 65.70; H, 6.40; N,5.85%. Found: C, 65.77; H, 6.37; N, 5.64%.

EXAMPLE 6

(5S,1'S)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline

Water (155 ml), toluene (100 ml), and anhydrous sodium carbonate (13.68g, 129 mmol) were added to(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (38.92 g, 86.0 mmol) prepared in Example 1 (B) andthe mixture was stirred at room temperature. Di-tert-butyldicarbonate(19.72 g, 90.4 mmol) in toluene (50 ml) was added dropwise at roomtemperature over 20 minutes. The mixture was further stirred overnightat room temperature and then extracted with toluene, and the aqueouslayer was extracted with toluene (100 ml). The toluene layers werecombined together and washed with saturated aqueous sodium bicarbonate,followed by concentration under reduced pressure to give 32.8 g ofresidue. The residue (30.79 g) was recrystallized from hexane (200 ml)to give the desired compound as colorless crystals. Yield: 28.35 g(87%). m.p. 94.0-95.0° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.31-7.18(m, 10H), 4.70(d,1H, J=10.0 Hz),4.49(broad t, 1H), 3.86(broad q, 1H), 3.64(d, 1H, J=14.7 Hz), 3.62(d,1H, J=14.7 Hz), 2.91 (dd, 1H, J=13.4, 6.8 Hz), 2.86(dd, 1H, J=13.4, 9.0Hz), 2.76(dd, 1H, J=17.5, 11.0 Hz), 2.67(dd, 1H, J=17.5, 8.6 Hz),1.36(s, 9H). IR(KBr, cm⁻¹)3389, 1698, 1504, 1245, 1170, 858, 700. α!_(D)²⁵ +89° (c=1.2, CH₃ OH). Mass spectrum (FD):m/z 380(M⁺). Anal. Calcd.for C₂₃ H₂₈ N₂ O₃ : C, 72.61; H, 7.42; N, 7.36%. Found: C, 72.68; H,7.42; N, 7.34%.

EXAMPLE 7

(5RS,1'RS)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 weresuspended in tetrahydrofuran (10 ml) and cooled with ice. To theresulting suspension, triethylamine (56 mg, 0.55 mmol) was added.Di-tert-butyldicarbonate (120 mg, 0.55 mmol) was added and the mixturewas stirred at room temperature for 4 hours. The reaction mixture wasconcentrated under reduced pressure. To the residue, water and ethylacetate were added for liquid separation. The organic layer was washedwith saturated aqueous sodium bicarbonate and then with water, followedby drying over anhydrous magnesium sulfate. After the desiccant wasfiltered off, the filtrate was concentrated to give an oil, to whichhexane was added for crystallization. Crude crystals were recrystallizedfrom diisopropyl ether/hexane to give the desired compound as colorlesscrystals. Yield: 148 mg (71%). m.p. 106.0-107.3° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.31-7.18(m, 10H), 4.70(d, 1H, J=10.0 Hz),4.49(broad t, 1H), 3.86(broad q, 1H), 3.64(d, 1H, J=14.7 Hz), 3.62(d,1H, J=14.7 Hz), 2.91 (dd, 1H, J=13.4, 6.8 Hz), 2.86(dd, 1H, J=13.4, 9.0Hz), 2.76(dd, 1H, J=17.5, 11.0 Hz), 2.67(dd, 1H, J=17.5, 8.6 Hz),1.36(s, 9H). IR(KBr, cm⁻¹)3394, 1687, 1510, 1494, 1248, 1163, 861, 700

EXAMPLE 8

(5S,1'S)-3-Phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazoline

(S)-3-Phthalimido-4-phenyl-1-butene (700 mg, 2.52 mmol) prepared in amanner similar to that described in Example 2 (A) andphenylacetohydroximoyl chloride (816 mg, 5.04 mmol) were dissolved intoluene (10 ml). To the resulting solution, anhydrous calcium carbonate(1.0 g, 10.0 mmol) and water (10 ml) were added and the mixture wasstirred at room temperature. In the course of stirring,phenylacetohydroximoyl chloride (400 mg) in toluene (10 ml) were furtheradded dropwise. After completion of reaction, the reaction mixture wasfiltered using Celite. The filtrate was washed with water and dried overanhydrous magnesium sulfate. After the desiccant was filtered off, thefiltrate was concentrated under reduced pressure to obtain an oil (1.9g) containing(5S,1'S)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazolineand(5R,1'S)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazoline.Reversed phase HPLC revealed that the ratio of(5S,1'S)-3-phenylmethyl-5-(1-phthalimido-2'-phenylethyl)-2-isoxazolineto(5R,1'S)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazolinewas 6:4. A half portion of the oil (1.9 g) was purified by silica gelcolumn chromatography (solvent for elution, hexane:ethyl acetate=4:1) togive the desired compound as colorless crystals. Yield: 270 mg. Thecrude crystals were recrystallized from diisopropyl ether. Yield: 180mg. m.p. 114.0-115.5° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.74(m,2H), 7.65(m, 2H), 7.36-7.04(m,10H), 5.15(dt, 1H), 4.47(ddd, 1H, J=9.0 Hz), 3.71(d, 1H, J=14.8 Hz),3.68(d, 1H, J=14.8 Hz), 3.34(dd, 1H, J=14.0, 11.2 Hz), 2.97(dd, 1H,J=17.2, 10.3 Hz), 2.91 (dd, 1H, J=14.0, 4.8 Hz), 2.70(dd, 1H, J=17.2,7.4 Hz). IR(KBr, cm⁻¹)1708, 1388, 720, 707. α!_(D) ²⁵ +100° (c=1.3,CHCl₃). Mass spectrum (FD):m/z 410(M⁺). Anal. Calcd. for C₂₆ H₂₂ N₂ O₃ :C, 76.08; H, 5.40; N, 6.82%. Found: C,75.98; H,5.33; N,6.75%.

EXAMPLE 9

(A) (RS)-3-Phthalimido-4-phenyl-1-butene

(RS)-3-Amino-4-phenyl-1-butene (1.2 g, 8.0 mmol) was dissolved intetrahydrofuran (20 ml). To the solution, a solution ofN-carbethoxyphthalimido (2.2 g, 10.0 mmol) in water (20 ml) andanhydrous sodium carbonate (1.06 g, 10.0 mmol) was added and stirred atroom temperature for 1 hour. The reaction mixture was concentrated underreduced pressure to remove tetrahydrofuran, followed by extraction withethyl acetate.

The organic layer was washed successively with 1M hydrochloric acid,saturated aqueous sodium bicarbonate, and saturated brine, and driedover anhydrous sodium sulfate. After the desiccant was filtered off, thefiltrate was concentrated under reduced pressure. The obtained paleyellow crystals were separated and purified by silica gel columnchromatography (solvent for elution, hexane:ethyl acetate=9:1) to givethe desired compound as colorless crystals. Yield: 2.1 g (93%).

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.75(m, 2H), 7.65(m, 2H), 7.19-7.11(m,5H), 6.27(ddd, 1H, J=1.72, 10.3, 7.2 Hz), 5.22(d, 1H, J=17.2 Hz),5.19(d, 1H, J=10.3 Hz), 5.05(ddd. 1H), 3.42(dd, 1H, J=13.8, 9.9 Hz),3.21(d, 1H, J=13.8, 6.5 Hz).

(B)(5RS,1'RS)-3-Phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazoline

(RS)-3-Phthalimido-4-phenyl-1-butene (558 mg, 2.01 mmol) obtained inExample 9 (A) and phenylacetohydroximoyl chloride (512 mg, 3.02 mmol)prepared in a manner similar to that described in Example 2 (B) weredissolved in diethyl ether (10 ml). To the solution, triethylamine (336mg, 3.32 mmol) in diethyl ether (10 ml) was added dropwise at roomtemperature over 3 hours. The mixture was stirred at room temperaturefor 1 hour, and then water and diethyl ether were added for liquidseparation. The separated organic layer was washed with saturated brineand dried over anhydrous sodium sulfate. After the desiccant wasfiltered off, the filtrate was concentrated under reduced pressure togive an oil (0.91 g) containing(5RS,1'RS)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazolineand(5RS,1'SR)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazoline.Reversed phase HPLC revealed that the ratio of(5RS,1'RS)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazolineto(5RS,1'SR)-3-phenylmethyl-5-(1'-phthalimido-2'-phenylethyl)-2-isoxazolinewas 6:4. The oil (0.91 g) was separated by silica gel columnchromatography (solvent for elution, hexane:ethyl acetate=4:1) to givethe desired compound as colorless crystals. Yield: 340 mg (41%). Foranalysis, part of the compound was recrystallized from diisopropylether/hexane. m.p. 134.0-135.5° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.74(m, 2H), 7.65(m, 2H), 7.36-7.04(m,10H), 5.15(dt, 1H), 4.47(ddd, 1H, J=9.0 Hz), 3.71(d, 1H, J=14.8 Hz),3.68(d, 1H, J=14.8 Hz), 3.34(dd, 1H, J=14.0, 11.2 Hz), 2.97(dd, 1H,J=17.2, 10.3 Hz), 2.91(dd, 1H, J=14.0, 4.8 Hz), 2.70(dd, 1H, J=17.2, 7.4Hz). IR(KBr, cm⁻¹)1770, 1710, 1381, 726, 703.

EXAMPLE 10

(5S,1'S)-3-Phenylmethyl-5-(1'-benzyloxycarbonylamino-2'-phenylethyl)-2-isoxazoline

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (300 mg, 0.66 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in tetrahydrofuran andcooled with ice. To the suspension, triethylamine (142 mg, 1.4 mmol) andbenzyl chloroformate (124 mg, 0.73 mmol) were added, then the mixturewas stirred for 2 hours. The reaction mixture was concentrated underreduced pressure. To the residue, water and ethyl acetate were added forliquid separation. The organic layer was washed with saturated aqueoussodium bicarbonate and then with water, followed by drying overanhydrous magnesium sulfate. After the desiccant was filtered off, thefiltrate was concentrated to give an oil. The oil was crystallized fromdiisopropyl ether/hexane to give the desired compound as colorlesscrystals. Yield: 145 mg (53%). m.p. 80.5-82.0° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.37-7.14(m, 15H), 5.03(d, 1H, J=12.4 Hz),4.97(d, 1H, J=12.4 Hz), 4.95(d, 1H, J=9.9 Hz), 4.51(broad t, 1H),3.93(broad q, 1H), 3.59(d, 1H, J=14.9 Hz), 3.51(d, 1H, J=14.9 Hz),2.93(dd, 1H, J=13.6, 7.1 Hz), 2.88(dd, 1H, J=13.6, 8.9 Hz), 2.77(dd, 1H,J=17.8, 11.5 Hz), 2.65(dd, 1H, J=17.8, 8.1 Hz). IR(KBr, cm⁻¹)3370, 1702,1521, 1494, 1453, 1252, 1237, 1046, 750, 700. α!_(D) ²⁵ +84° (c=1.1, CH₃OH). Mass spectrum (FD):m/z 414(M⁺). Anal. Calcd. for C₂₆ H₂₆ N₂ O₃ : C,75.34; H, 6.32; N, 6.76%. Found: C, 75.47; H, 6.42; N, 6.90%.

EXAMPLE 11

(5RS,1'RS)-3-Phenylmethyl-5-(1'-benzyloxycarbonylamino-2'-phenylethyl)-2-isoxazoline

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 wassuspended in tetrahydrofuran (10 ml) and cooled with ice. To thesuspension, triethylamine (111 mg, 1.10 mmol) and chloroformate (94 mg,0.55 mmol) were added and stirred at room temperature for 4 hours. Thereaction mixture was concentrated under reduced pressure. To theresidue, water and ethyl acetate were added for liquid separation. Theorganic layer was washed with saturated aqueous sodium bicarbonate andthen with water, and dried over anhydrous magnesium sulfate. After thedesiccant was filtered off, the filtrate was concentrated to give anoil. Hexane was added to the oil for crystallization. Crude crystalswere recrystallized from diisopropyl ether/hexane to give the desiredcompound as colorless crystals. Yield: 167 mg (61%). m.p. 87.5-89.5° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.37-7.14(m, 15H), 5.03(d, 1H, J=12.4 Hz),4.97(d, 1H, J=12.4 Hz), 4.95(d, 1H, J=9.9 Hz), 4.51(broad t, 1H),3.93(broad q, 1H), 3.59(d, 1H, J=14.9 Hz), 3.51(d, 1H, J=14.9 Hz),2.93(dd, 1H, J=13.6, 7.1 Hz), 2.88(dd, 1H, J=13.6, 8.9 Hz), 2.77(dd, 1H,J=17.8, 11.5 Hz), 2.65(dd, 1H, J=17.8, 8.1 Hz). IR(KBr, cm⁻¹)3250, 1702,1547, 1495, 1453, 1256, 730, 699.

EXAMPLE 12

(5RS,1'RS)-3-Phenylmethyl-5-(1'-benzyloxycarbonylamino-2'-phenylethyl)-2-isoxazoline

Toluene (12 ml) solution phenylacetohydroximoyl chloride (0.264 g, 1.56mmol) obtained in a manner similar to that described in Example 2 (B)was added dropwise to the toluene (4 ml) solution of(RS)-3-benzyloxycarbonylamino-4-phenyl-1-butene (0.288 g. 1.0 mmol) andtriethylamine (0.190 g, 1.88 mmol) over 1.25 hours while cooling in anice-water bath. After stirring for 1.65 hours in an ice-water bath andfor 2 hours at room temperature, water was added, followed by extractionwith diisopropyl ether. The organic layer was dried over anhydrousmagnesium sulfate, and then After the desiccant was filtered off, thefiltrate was concentrated under reduced pressure to give yellow liquid(0.53 g). The liquid was purified by silica gel column chromatography(solvent for elution, ethyl acetate/hexane=1/7 to 1/4) to give thedesired compound (0.22 g, 52%) as yellow liquid. Part of the yellowliquid was recrystallized from diisopropyl ether/hexane to give thedesired compound as colorless crystals.

The thus obtained compound agreed with the compound obtained in Example11.

EXAMPLE 13

(5S,1'S)-3-Phenylmethyl-5-(1'-methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (300 mg, 0.66 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in tetrahydrofuran (5 ml)and cooled with ice, and triethylamine (142 mg, 1.4 mmol) was added. Tothe mixture, methyl chloroformate (70 mg, 0.73 mmol) was added and themixture was stirred for 2 hours. The reaction mixture was concentratedunder reduced pressure. To the residue, water and ethyl acetate wereadded for separation. The organic layer was washed with saturatedaqueous sodium bicarbonate and then with water, followed by drying overanhydrous magnesium sulfate. After the desiccant was filtered off, thefiltrate was concentrated to give an oil. The oil was crystallized fromdiisopropyl ether/hexane to give the desired compound as colorlesscrystals. Yield: 146 mg (65%). m.p. 90.5-93.0° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.30-7.17(m, 10H), 4.83(d, 1H, J=10.0 Hz),4.51(m, 1H), 3.89(broad q, 1H), 3.64(d, 1H, J=14.6 Hz), 3.61(d, 1H,J=14.6 Hz), 3.57(s, 3H), 2.91(dd, 1H, J=13.5, 6.7 Hz), 2.87(dd, 1H,J=13.5, 9.1 Hz), 2.78(dd, 1H, J=17.4, 11.0 Hz) 2.65(dd, 1H, J=17.4, 8.0Hz). IR(KBr, cm⁻¹)3382, 1702, 1522, 1245, 1059, 727, 701. α!_(D) ₂₅ +89°(c=1.0, CH₃ OH). Mass spectrum (FD): m/z 338(M⁺). Anal. Calcd. for C₂₀H₂₂ N₂ O₃ : C, 70.99; H, 6.55; N, 8.28%. Found: C, 71.16; H, 6.56; N,8.19%.

EXAMPLE 14

(5RS,1'RS)-3-Phenylmethyl-5-(1'-methoxycarbonylamino-2'-phenylethyl)-2-isoxazoline

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 wassuspended in tetrahydrofuran (5 ml) and cooled with ice. To thesuspension, triethylamine (122 mg, 1.21 mmol) and methyl chloroformate(62 mg, 0.66 mmol) were added and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated underreduced pressure. To the residue, water and ethyl acetate were added forliquid separation. The separated organic layer was washed with saturatedaqueous sodium bicarbonate and then with water, followed by drying overanhydrous magnesium sulfate. After the desiccant was filtered off, thefiltrate was concentrated to obtain an oil. The oil was crystallizedfrom diisopropyl ether/hexane to give the desired compound as colorlesscrystals. Yield: 136 mg (73%). m.p. 87.0 to 88.5° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.30-7.17(m, 10H), 4.83(d, 1H, J=10.0 Hz),4.51 (m, 1H), 3.89(broad q, 1H), 3.64(d, 1H, J=14.6 Hz), 3.61(d, 1H,J=14.6 Hz), 3.57(s, 3H), 2.91(dd, 1H, J=13.5, 6.7 Hz), 2.87(dd, 1H,J=13.5, 9.1 Hz), 2.78(dd, 1H, J=17.4, 11.0 Hz), 2.65(dd, 1H, J=17.4, 8.0Hz). IR(KBr, cm⁻¹) 3277, 1707, 1702, 1534, 1252, 1047, 704.

EXAMPLE 15

(5S,1'S)-3-Phenylmethyl-5-(1-formylamino-2'-phenylethyl)-2-isoxazoline

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (300 mg, 0.66 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in tetrahydrofuran (5 ml)and cooled with ice. To the suspension, triethylamine (67 mg, 0.66 mmol)and formic acid (37 mg, 0.8 mmol) were added, and then1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (127 mg,0.66 mmol) was added. The resulting mixture was stirred for 2 hours onice and then for 1 hour at room temperature, then concentrated underreduced pressure. A 10% aqueous citric acid and ethyl acetate were addedto the residue for liquid separation. The organic layer separated waswashed with saturated aqueous sodium bicarbonate and then with water,followed by drying over anhydrous magnesium sulfate. After the desiccantwas filtered off, the filtrate was concentrated to give an oil. To theoil, hexane was added and crystals were obtained. Crude crystals wererecrystallized from ethyl acetate/hexane to give the desired compound ascolorless crystals. Yield: 146 mg (72%). m.p. 94.5-95.8° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.93(s, 1H), 7.32-7.14(m, 10H), 5.64(d,1H, J=9.6 Hz), 4.54(dd, 1H), 4.34(broad q, 1H), 3.61(s, 2H), 2.91(d, 2H,J=8.0 Hz), 2.85(dd, 1H, J=17.5, 11.1 Hz), 2.63(dd, 1H, J=17.5, 7.6 Hz).IR(KBr, cm⁻¹)3345, 1651, 1514, 1386, 1234, 718, 699. α!_(D) ²⁵ +79°(c=1.1, CH₃ OH). Mass spectrum (FD):m/z 308(M⁺). Anal. Calcd. for C₁₉H₂₀ N₂ O₂ : C, 74.00; H, 6.54; N, 9.08%. Found: C, 73.80; H,6.54;N,8.91%.

EXAMPLE 16

(5RS,1'RS)-3-Phenylmethyl-5-(1'-formylamino-2'-phenylethyl)-2-isoxazoline

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 wassuspended in tetrahydrofuran (5 ml) and cooled with ice. To thesuspension, triethylamine (56 mg, 0.55 mmol) and formic acid (30 mg,0.65 mmol) were added, then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (127 mg, 0.66 mmol) was added. The mixturewas stirred at room temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure. To the residue, water and ethylacetate were added for liquid separation. The organic layer separatedwas washed successively with a 10% aqueous citric acid, saturatedaqueous sodium bicarbonate, and water, followed by drying over anhydrousmagnesium sulfate. After the desiccant was filtered off, the filtratewas concentrated to give an oil. To the oil, hexane was added andcrystals were obtained. Crude crystals were recrystallized from ethylacetate/diisopropyl ether to give the desired compound as colorlesscrystals. Yield: 115 mg (68%). m.p. 112.0 to 113.0° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.93(s, 1H), 7.32-7.14(m, 10H), 5.64(d,1H, J=9.6 Hz), 4.54(dd, 1H), 4.34(broad q, 1H), 3.61(s,2H), 2.91(d, 2H,J=8.0 Hz), 2.85(dd, 1H, J=17.5, 11.1 Hz), 2.63(dd, 1H, J=17.5, 7.6 Hz).IR(KBr, cm⁻¹)3209, 3027, 1658, 1545, 1385, 894, 702.

EXAMPLE 17

(5S,1'S)-3-Phenylmethyl-5-(1'-acetylamino-2'-phenylethyl)-2-isoxazoline

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (300 mg, 0.66 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in ethanol (5 ml). To thesuspension, anhydrous sodium acetate (65 mg, 0.8 mmol) and aceticanhydride (65 mg, 0.8 mmol) were added. The mixture was stirred at roomtemperature for 15 minutes, then concentrated under reduced pressure.Water and ethyl acetate were added to the residue for liquid separation.The organic layer separated was washed with saturated aqueous sodiumbicarbonate and then with water, followed by drying over anhydrousmagnesium sulfate. After the desiccant was filtered off, the filtratewas concentrated to give crude crystals. The crude crystals wererecrystallized from hexane/ethyl acetate to give the desired compound ascolorless crystals. Yield: 170 mg (80%) m.p. 124.4 to 125.2° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.31-7.18(m, 10H) 5.54(d, 1H, J=9.5 Hz),4.52(ddd, 1H, J=1.0 Hz), 4.26(broad q, 1H),3.62(d, 1H, J=14.7 Hz),3.59(d, 1H, J=14.7 Hz), 2.88(dd, 1H, J=13.7, 7.5 Hz), 2.87(dd, 1 H,J=13.7, 8.7 Hz), 2.82(dd,J1H, J=17.6, 11.1 Hz), 2.64(dd, 1H, J=17.6, 7.9Hz), 1.77(s,3H). IR(KBr, cm⁻¹)3367, 1651, 1526, 700. α!_(D) ²⁵ +68°(c=1.2, CH₃ OH). Mass spectrum (FD):m/z 322(M⁺). Anal. Calcd. for C₂₀H₂₂ N₂ O₂ : C, 74.51; H, 6.88; N, 8.69%. Found: C, 74.41; H, 6.67; N,8.64%.

EXAMPLE 18

(5RS,1'RS)-3-Phenylmethyl-5-(1'-acetylamino-2'-phenylethyl)-2-isoxazoline

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 wassuspended in ethanol (10 ml). To the suspension, anhydrous sodiumacetate (45 mg, 0.55 mmol) and acetic anhydride (56 mg, 0.55 mmol) wereadded. The mixture was stirred at room temperature for 15 minutes, thenconcentrated under reduced pressure. Water and ethyl acetate were addedto the residue for liquid separation. The organic layer was washed withsaturated anhydrous sodium bicarbonate and then with water, followed bydrying over anhydrous magnesium sulfate. The desiccant was filtered off.After the filtrate was concentrated to give crude crystals, the crudecrystals were recrystallized from hexane/ethyl acetate to give thedesired compound as colorless crystals. Yield: 147 mg (83%). m.p.97.8-98.4° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.31-7.18(m, 10H), 5.54(d, 1H, J=9.5 Hz),4.52(ddd, 1H, J=1.0 Hz), 4.26(broad q, 1H), 3.62(d, 1H, J=14.7 Hz),3.59(d, 1H, J=14.7 Hz), 2.88(dd, 1H, J=13.7, 7.5 Hz), 2.87(dd, 1H,J=13.7, 8.7 Hz), 2.82(dd, 1H, J=17.6, 11.1 Hz), 2.64(dd, 1H, J=17.6, 7.9Hz), 1.77(s, 3H). IR(KBr, cm⁻¹)3368, 1651, 1526, 700.

EXAMPLE 19

(5S,1'S)-3-Phenylmethyl-5-(1'-benzoylamino-2'-phenylethyl)-2-isoxazoline

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (300 mg, 0.66 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in tetrahydrofuran (5 ml)and cooled with ice. To the suspension, triethylamine (142 mg, 1.4 mmol)and benzoyl chloride (102 mg, 0.73 mmol) were added. The mixture wasstirred at room temperature for 2 hours and the reaction mixture wasconcentrated under reduced pressure. Water and ethyl acetate were addedto the residue for liquid separation. The organic layer separated waswashed with saturated sodium bicarbonate water and then with water,followed by drying over anhydrous magnesium sulfate. After the desiccantwas filtered off, the filtrate was concentrated to give crude crystals.The crude crystals were recrystallized from hexane/ethyl acetate to givethe desired compound as colorless crystals. Yield: 224 mg (88%). m.p.147.0-148.2° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.63(d, 2H), 7.52(t 1H), 7.43(t, 2H),7.31-7.05(m, 10H), 6.26(d, 1H, J=9.8 Hz), 4.63(dd, 1H), 4.50(broad q,1H), 3.58(d, 1H, J=14.9 Hz), 3.54(d, 1H, J=14.9 Hz), 3.03(dd, 1 H,J=13.6, 6.9 Hz), 2.98(dd, 1H, J=13.6, 9.1 Hz), 2.85(dd, 1H, J=17.7, 11.1Hz), 2.72(dd, 1H, J=17.7, 7.9 Hz). IR(KBr, cm⁻¹)3373, 1643, 1518, 726,695. α!_(D) ²⁵ +109° (c=1.2, CHCl₃). Mass spectrum (FD):m/z 384(M⁺).Anal. Calcd. for C₂₅ H₂₄ N₂ O₂ : C, 78.10; H, 6.29; N, 7.29%. Found: C,78.03; H,6.29; N, 7.16%.

EXAMPLE 20

(5RS,1'RS)-3-Phenylmethyl-5-(1'-benzoylamino-2'-phenylethyl)-2-isoxazoline

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 wassuspended in tetrahydrofuran (10 ml) and cooled with ice. To thesuspension, triethylamine (111 mg, 1.1 mmol) and benzoyl chloride (77mg, 0.55 mmol) were added. The mixture was stirred at room temperaturefor 4 hours, then concentrated under reduced pressure. Water and ethylacetate were added to the residue for liquid separation. The organiclayer separated was washed with saturated aqueous sodium bicarbonate andthen with water, followed by drying over anhydrous magnesium sulfate.After the desiccant was filtered off, the filtrate was concentrated togive crude crystals. The crude crystals were recrystallized fromhexane/ethyl acetate to give the desired compound as colorless crystals.Yield: 172 mg (81%). m.p. 140.9-141.7° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.63(d, 2H), 7.52(t, 1H), 7.43(t, 2H),7.31-7.05(m, 10H), 6.26(d, 1H, J=9.8 Hz), 4.63(dd, 1H), 4.50(broad q,1H), 3.58(d, 1H, J=14.9 Hz), 3.54(d, 1H, J=14.9 Hz), 3.03(dd, 1H,J=13.6, 6.9 Hz), 2.98(dd, 1H, J=13.6, 9.1 Hz), 2.85(dd, 1H, J=17.7, 11.1Hz), 2.72(dd, 1H, J=17.7, 7.9 Hz). IR(KBr, cm⁻¹)3333, 1638, 1540, 701,694.

EXAMPLE 21

(5S,1'S)-3-Phenylmethyl-5-(1'-N,N-dibenzylamino-2'-phenylethyl)-2-isoxazoline

Potassium carbonate (31.9 g, 301 mmol), water (47.8 g), and benzylchloride (35.3 g, 279 mmol) were added to(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline (28.5g, 102 mmol) prepared from(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate prepared in a manner similar to that described inExample 1 (B). The resulting mixture was stirred at 80° CC. for 63hours. Toluene (516 g) was added to the reaction mixture, the mixturethus obtained was separated, and the organic layer separated was washedwith water (285 g). The organic layer was concentrated under reducedpressure to give an oil (59 g). The oil (55 g) was crystallized fromisopropyl alcohol (330 ml) to give the desired compound as colorlesscrystals. Yield: 37.68 g (87%). m.p. 125.5-126.4° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.33-7.11(m, 20H), 4.46(dt, 1H, J=10.8,4.0 Hz), 4.06(d, 2H, J=13.5 Hz), 3.66(s, 2H), 3.54(d, 2H, J=13.5 Hz),3.07(dd, 1H, J=13.1, 5.0 Hz), 2.91 (m, 2H), 2.41 (dd, 2H, J=16.9, 10.8Hz). IR(KBr, cm⁻¹)3022, 2803, 1495, 1453, 857, 756, 701. Mass spectrum(FD):m/z 461(M⁺ +H).

EXAMPLE 22

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (200 mg, 0.44 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in methylene chloride (25ml). To the suspension, a 10% aqueous sodium hydroxide (8 ml) was addedto neutralize the sulfonate, followed by liquid separation. After theorganic layer was washed and dried over anhydrous magnesium sulfate.After the desiccant was filtered off, the filtrate was concentratedunder reduced pressure to give colorless crystals. Yield; 120 mg (97%).m.p. 47.0 to 49.0° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.34-7.15(m, 10H), 4.45(ddd, 1H),3.68(s,2H), 2.90(dt, 1H, J=4.8 Hz), 2.82(dd,₁ H, J=17.1, 10.6 Hz),2.78(dd, 1H, J=13.4, 4.5 Hz), 2.75(dd, 1H, J=17.1, 8.2 Hz), 2.55(dd, 1H,J=13.4, 8.9 Hz). IR(KBr, cm⁻¹)3028, 2921, 1563, 1495, 1453, 872, 857,826, 733, 707, 697. α!_(D) ²⁵ +152° (c=1.0, CH₃ OH). Mass spectrum(FD):m/z 281(M⁺ +H). Anal. Calcd. for C₁₈ H₂₀ N₂ O: C, 77.11; H, 7.19;N, 9.99%. Found: C, 77.29; H,7.29; N, 9.93%.

EXAMPLE 23

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (200 mg, 0.44 mmol) prepared in Example 5 wassuspended in methylene chloride (25 ml). To the suspension, a 10%aqueous sodium hydroxide (8 ml) was added to neutralize the sulfonate,followed by liquid separation. After the organic layer was washed withwater and dried over anhydrous magnesium sulfate. After the desiccantwas filtered off, the filtrate was concentrated under reduced pressureto give an oil. Yield 130 mg.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.34-7.15(m, 10H), 4.45(ddd, 1H), 3.68(s,2H), 2.90(dt, 1H, J=4.8 Hz), 2.82(dd, 1H, J=17.1, 10.6 Hz), 2.78(dd, 1H,J=13.4, 4.5 Hz), 2.75(dd, 1H, J=17.1, 8.2 Hz), 2.55(dd, 1H, J=13.4, 8.9Hz) IR(KBr, cm⁻¹)3026, 2917, 1602, 1583, 1494, 1454, 860, 745, 701

EXAMPLE 24

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinehydrochloride

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in ethyl acetate (25 ml).To the suspension, a 10% aqueous sodium hydroxide (8 m) was added toneutralize the sulfonate, followed by liquid separation. After theorganic layer was washed with water and dried over anhydrous magnesiumsulfate. After the desiccant was filtered off, the filtrate wasconcentrated under reduced pressure. The resulting oil containing(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline wasdissolved in ethanol (5 ml), and conc. hydrochloric acid (0.1 ml) wasadded. The mixture was concentrated under reduced pressure. Ethanol andtoluene were added to the residue, followed by concentration underreduced pressure. Crude crystals of the residue were recrystallized fromethanol/ethyl acetate to give the desired compound as colorlesscrystals. Yield: 105 mg (60%). m.p. 188.0-190.5° C. (decomposed).

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7.34-7.18(m, 10H), 4.53(dt, 1H, J=7.7Hz), 3.67(d, 1H, J=14.9 Hz), 3.66(d, 1H, J=14.9 Hz), 3.44(q, 1H),2.98(dd, 1H, J=17.7, 10.7 Hz), 2.93(dd, 1H, J=14.2, 6.7 Hz), 2.86(dd,1H, J=14.2, 7.4 Hz), 2.62(dd 1H, J=17.7, 7.4 Hz). IR(KBr, cm⁻¹)3026,2877, 1604, 1581, 1510, 1493, 1455, 862, 703 α!_(D) ²⁵ +113° (c=1.0, CH₃OH). Mass spectrum (FD):m/z 281(M⁺ -Cl). Anal. Calcd. for the adduct C₁₈H₂₁ N₂ OCl 0.25H₂ O: C, 67.28; H, 6.74; N, 8.72%. Found: C, 67.28; H,6.64; N, 8.71%.

EXAMPLE 25

(A)(5S,1'S)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolineand

(5R,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline

(S)-3-tert-butoxycarbonylamino-4-phenyl-1-butene (1.236 g, 5 mmol) andphenylacetohydroximoyl chloride (1.701 g. 10 mmol) obtained in a mannersimilar to that described in Example 2 (B) were dissolved in toluene (6ml). To the solution, triethylamine (1.219 g, 12 mmol) in toluene (12ml) was added dropwise at room temperature over 2 hours. After themixture was stirred at room temperature for 1.5 hour, water was added,followed by extraction with additional toluene. The organic phase wasconcentrated under reduced pressure to give a yellow liquid (2.90 g)containing(5S,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolineand(5R,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline.Reversed phase HPLC revealed that the ratio of (5S,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolineto(5R,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolinewas 7:3. This yellow liquid was used in the next step withoutpurification.

(B) (5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolineand (5R,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline

A liquid (2.69 g) containing(5S,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolineand(5R,1'S)-3-phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazolineobtained in Example 25 (A) was dissolved in methylene chloride (8 ml).To the solution, trifluoroacetic acid (4 ml) was added at roomtemperature. After the mixture was stirred at room temperature for 35minutes, a 10% aqueous sodium hydroxide was added. After extraction withmethylene chloride, the mixture was dried over anhydrous magnesiumsulfate. After the desiccant was filtered off, the filtrate wasconcentrated under reduced pressure to give a yellow liquid (2.04 g)containing the desired compound. This yellow liquid was used in the nextstep without purification.

(C) (5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinehydrochloride

A liquid (2.04 g) containing(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline and(5R,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolineobtained in Example 25 (B) was dissolved in isopropyl alcohol (20 ml).Hydrogen chloride gas was added into the solution at room temperature.The resulting solution was heated to dissolve, and then diisopropylether (10 ml) was added thereto, followed by cooling. Crystalsprecipitated were filtered under reduced pressure, and washed withisopropyl alcohol/diisopropyl ether (1/1). From a solid (0.700 g)obtained by drying under reduced pressure, a portion of 0.600 g wasrecrystallized from isopropyl alcohol to give the desired compound aslight khaki crystals (0.325 g).

The obtained compound agreed with the compound obtained in Example 24.

EXAMPLE 26

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinehydrochloride

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 wassuspended in ethyl acetate (25 ml). To the suspension, a 10% aqueoussodium hydroxide (8 ml) was added to neutralize the sulfonate, followedby liquid separation. After the organic layer was washed with water anddried over anhydrous magnesium sulfate. After the desiccant was filteredoff, the filtrate was concentrated under reduced pressure. The resultingoil containing(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline wasdissolved in ethanol (5 ml), and conc. hydrochloric acid (0.1 ml) wasadded. After the mixture was concentrated under reduced pressure,ethanol and toluene were added to the residue, followed by concentrationunder reduced pressure. Residual crude crystals were recrystallized fromethanol/diisopropyl ether to give the desired compound as colorlesscrystals. Yield: 146 mg (84%). m.p. 196.0-198.0° C. (decomposed).

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7.34-7.18(m, 10H), 4.53(dt, 1H, J=7.7Hz), 3.67(d, 1H, J=14.9 Hz), 3.66(d, 1H, J=14.9 Hz), 3.44(q, 1H),2.98(dd, 1H, J=17.7, 10.7 Hz), 2.93(dd, 1H, J=14.2, 6.7 Hz), 2.86(dd,1H, J=14.2, 7.4 Hz), 2.62(dd, 1H, J=17.7, 7.4 Hz). IR(KBr, cm⁻¹)3027,2926, 1604, 1578, 1508, 1494, 1455, 859, 700

EXAMPLE 27

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinebenzenesulfonate

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in ethyl acetate (25 ml).To the suspension, a 10% aqueous sodium hydroxide (8 ml) was added toneutralize the sulfonate, followed by liquid separation. After theorganic layer was washed and dried over anhydrous magnesium sulfate.After the desiccant was filtered off, the filtrate was concentratedunder reduced pressure. The resulting oil containing(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline wasdissolved in a small amount of ethanol. Benzenesulfonic acid monohydrate(104 mg, 0.6 mmol) was added to the solution for crystallization. Thecrystals were recrystallized from ethanol/ethyl acetate to give thedesired compound as colorless crystals. Yield: 165 mg (68%) m.p. 218.0to 219.0° C. (decomposed).

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7.84-7.18(m, 15H), 4.53(dt, 1H), 3.67(d,1H, J=14.9 Hz), 3.64(d, 1H, J=14.9 Hz), 3.45(q, 1H, J=7.6 Hz), 2.94(dd.1H, J=17.7, 10.7 Hz), 2.90(dd, 1H, J=14.5, 7.2 Hz), 2.87(dd, 1H, J=14.5,7.4 Hz), 2.62(dd, 1H, J=17.7, 7.6 Hz). IR(KBr, cm⁻¹)3052, 2925, 1633,1526, 1210, 1185, 1128, 1036, 1017, 729, 700, 690, 614, 569. α!_(D) ²⁵+84° (c=1.1, CH₃ OH). Mass spectrum (FD):m/z 281(M⁺ -PhSO₃). Anal.Calcd. for C₂₄ H₂₆ N₂ O₄ S: C, 65.73; H, 5.98; N, 6.39%. Found: C,65.98; H, 5.93; N, 6.14%.

EXAMPLE 28

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinebenzenesulfonate

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 wassuspended in ethyl acetate (25 ml). To the suspension, a 10% aqueoussodium hydroxide (8 ml) was added to neutralize the sulfonate, followedby liquid separation. After the organic layer was washed with water anddried over anhydrous magnesium sulfate. After the desiccant was filteredoff, the filtrate was concentrated under reduced pressure. The resultingoil containing(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline wasdissolved in a small amount of ethanol. Benzenesulfonic acid monohydrate(97 mg, 0.55 mol) was added to the solution for crystallization. Thecrystals were recrystallized from ethanol/ethyl acetate to givecolorless crystals. Yield: 198 mg (82%). m.p. 210.0-212.0° C.(decomposed).

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7.84-7.18(m, 15H), 4.53(dt,1H), 3.67(d,1H, J=14.9 Hz), 3.64(d, 1H, J=14.9 Hz), 3.45(q, 1H, J=7.6 Hz), 2.94(dd,1H, J=17.7, 10.7 Hz), 2.90(dd, 1H, J=14.5, 7.2 Hz), 2.87(dd, 1H, J=14.5,7.4 Hz), 2.62(dd, 1H, J=17.7, 7.6 Hz). IR(KBr, cm⁻¹)3063, 2948, 1637,1526, 1209, 1181, 1128, 1035, 1016, 729, 699, 690, 612.

EXAMPLE 29

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinemethanesulfonate

(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in ethyl acetate (25 ml).To the suspension, a 10% aqueous sodium hydroxide (8 ml) was added toneutralize the sulfonate, followed by liquid separation. After theorganic layer was washed with water and dried over anhydrous magnesiumsulfate. After the desiccant was filtered off, the filtrate wasconcentrated under reduced pressure. The resulting oil containing(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline wasdissolved in a small amount of ethanol. Methanesulfonic acid (57 mg, 0.6mmol) and diisopropyl ether were added to the mixture forcrystallization to give the desired compound. Crystals, thus obtained,was colorless. Yield: 116 mg (56%). m.p. 121.0-125.0° C. (decomposed).

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7.34-7.18(m, 10H), 4.52(dt, 1H), 3.67(d,1H, J=14.9 Hz), 3.66(d, 1H, J=14.9 Hz), 3.44(q, 1H, J=7.7 Hz), 2.98(dd.1H, J=17.8, 10.5 Hz), 2.93(dd, 1H, J=13.6, 6.7 Hz), 2.87(dd, 1H, J=13.6,7.3 Hz), 2.68(s, 3H), 2.61(dd, 1H, J=17.8, 7.5 Hz). IR(KBr, cm⁻¹)3025,2918, 1626, 1600, 1493, 1451, 1344, 1209, 1195, 1042, 859, 772, 701.α!_(D) ²⁵ +93° (c=1.1, CH₃ OH). Mass spectrum (FD):m/z 281(M⁺ -MsO).Anal. Calcd. for the adduct C₁₉ H₂₄ N₂ O₄ S.0.5H₂ O: C, 59.20; H, 6.54;N, 7.27% Found: C, 59.02; H, 6.43; N, 7.05%

EXAMPLE 30

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinemethanesulfonate

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 wassuspended in ethyl acetate (25 ml). To the suspension, a 10% aqueoussodium hydroxide (8 ml) was added to neutralize the sulfonate, followedby liquid separation. The organic layer separated was washed with waterand dried over anhydrous magnesium sulfate. After the desiccant wasfiltered off, the filtrate was concentrated under reduced pressure. Theresulting oil containing(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline wasdissolved in a small amount of ethanol. Methanesulfonic acid (53 mg,0.55 mmol) was added to the solution. The mixture was recrystallizedfrom ethanol/diisopropyl ether to give the desired compound as colorlesscrystals. Yield: 190 mg (92%). m.p. 159.0-161.0° C. (decomposed).

¹ H NMR(500 MHz,CD₃ OD) δ ppm 7.34-7.18(m, 10H), 4.52(dt, 1H), 3.67(d,1H, J=14.9 Hz), 3.66(d, 1H, J=14.9 Hz), 3.44(q, 1H, J=7.7 Hz), 2.98(dd,1H, J=17.8, 10.5 Hz), 2.93(dd, 1H, J=13.6, 6.7 Hz), 2.87(dd, 1H, J=13.6,7.3 Hz), 2.68(s, 3H), 2.61(dd, 1H, J=17.8, 7.5 Hz). IR(KBr, cm⁻¹)3027,2934, 1617, 1547, 1494, 1244, 1194, 1142, 1033, 702, 558.

EXAMPLE 31

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinebenzoate

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in ethyl acetate (25 ml).To the suspension, a 10% aqueous sodium hydroxide (8 ml) was added toneutralize the sulfonate, followed by liquid separation. The organiclayer was washed with water and dried over anhydrous magnesium sulfate.After the desiccant was filtered off, the filtrate was concentratedunder reduced pressure. The resulting oil containing(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline wasdissolved in a small amount of ethanol. Benzoic acid (72 mg, 0.6 mmol)was added to the solution and crystals were precipitated. The resultingcrude crystals were recrystallized from ethanol/diisopropyl ether togive the desired compound as colorless crystals. Yield: 135 mg (61%).m.p. 128.5-129.5° C.

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7.95(m, 2H), 7.44(m, 1H), 7.37(m, 2H),7.32-7.16(m, 10H), 4.48(dt, 1H, J=7.4 Hz), 3.66(d, 1H, J=14.9 Hz),3.65(d, 1H, J=14.9 Hz), 3.27(q, 1H), 2.92(dd, 1H, J=17.7, 10.7 Hz),2.85(dd, 1H, J=13.9, 6.4 Hz), 2.77(dd, 1 H, J=13.9, 7.7 Hz), 2.65(dd,1H, J=17.7, 7.8 Hz). IR(KBr, cm⁻¹)3058, 3027, 2917, 1629, 1592, 1565,1506, 1455, 1444, 1426, 1396, 1383, 719, 708, 696. α!_(D) ²⁵ +95°(c=1.2, CH₃ OH). Mass spectrum(FD):m/z 281(M⁺ -PhCOO). Anal. Calcd. forC₂₅ H₂₆ N₂ O₃ : C, 74.60; H, 6.51; N, 6.96%. Found: C, 74.35; H, 6.57;N, 6.80%.

EXAMPLE 32

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinebenzoate

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 wassuspended in ethyl acetate (25 ml). To the suspension, a 10% aqueoussodium hydroxide (8 ml) was added to neutralize the sulfonate, followedby liquid separation. The organic layer was washed with water and driedover anhydrous magnesium sulfate. After the desiccant was filtered off,the filtrate was concentrated under reduced pressure. The resulting oilcontaining(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline wasdissolved in a small amount of ethanol. Benzoic acid (72 mg, 0.6 mmol)was added to the solution and crystals were separated. The resultingcrude crystals were recrystallized from ethanol/diisopropyl ether togive the desired compound as colorless crystals. Yield: 131 mg (59%).m.p. 119.0-120.5° C.

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7.95(m, 2H), 7.44(m, 1H), 7.37(m, 2H),7.32-7.16(m, 10H), 4.48(dt, 1H, J=7.4 Hz), 3.66(d, 1H, J=14.9 Hz),3.65(d, 1H, J=14.9 Hz), 3.27(q, 1H), 2.92(dd, 1H, J=17.7, 10.7 Hz),2.85(dd, 1H, J=13.9, 6.4 Hz), 2.77(dd, 1H, J=13.9, 7.7 Hz), 2.65(dd, 1H,J=17.7, 7.8 Hz). IR(KBr, cm⁻¹)3057, 3027, 2921, 1629, 1592, 1563, 1496,1455, 1444, 1428, 1393, 1380, 719, 706.

EXAMPLE 33

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolineoxalate

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in a manner similar tothat described in Example 1 (B) was suspended in ethyl acetate (25 ml).To the suspension, a 10% aqueous sodium hydroxide (8 ml) was added toneutralize the sulfonate, followed by liquid separation. The organiclayer was washed with water and dried over anhydrous magnesium sulfate.After the desiccant was filtered off, the filtrate was concentratedunder reduced pressure. The resulting oil containing(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline wasdissolved in a small amount of ethanol. Oxalic acid dihydrate (74 mg,0.6 mmol) was added to the solution, and crystals were separated. Theresulting crude crystals were recrystallized from methanol/diisopropylether to give the desired compound as colorless crystals. Yield: 176 mg(86%). m.p. 190.0-191.0° C. (decomposed).

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7.33-7.18(m, 10H), 4.54(dt, 1H, J=7.6Hz), 3.66(d, 1H, J=14.9 Hz), 3.65(d, 1H, J=14.9 Hz), 3.45(q, 1H),2.96(dd, 1H, J=17.7, 10.7 Hz), 2.91(m, 2H, J=14.2, 7.2, 7.1 Hz),2.62(dd, 1H, J=17.7, 7.5 Hz). IR(KBr, cm⁻¹)3084, 3061, 3030, 2935, 1740,1702, 1677, 1604, 1533, 1493, 1455, 1444, 892, 857, 696. α!_(D) ²⁵ +99°(c=1.2, CH₃ OH). Mass spectrum (FD):m/z 281(M⁺ -C₂ HO₄). Anal. Calcd.for C₂₀ H₂₄ N₂ O₅ : C, 64.85; H, 5.99; N, 7.56%. Found: C, 64.64; H,5.97; N, 7.42%.

EXAMPLE 34

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolineoxalate

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolinep-toluenesulfonate (250 mg, 0.55 mmol) prepared in Example 5 wassuspended in ethyl acetate (25 ml). To the suspension, a 10% aqueoussodium hydroxide (8 ml) was added to neutralize the sulfonate, followedby liquid separation. The organic layer was washed with water and driedover anhydrous magnesium sulfate. After the desiccant was filtered off,the filtrate was concentrated under reduced pressure. The resulting oilcontaining(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline wasdissolved in a small amount of ethanol. Oxalic acid dihydrate (70 mg,0.55 mmol) was added to the solution and crystals were separated. Theresulting crude crystals were recrystallized from methanol/diisopropylether to give the desired compound as colorless crystals. Yield: 175 mg(86%). m.p. 176.0 to 177.5° C. (decomposed).

¹ H NMR(500 MHz, CD₃ OD) δ ppm 7.33-7.18(m, 10H), 4.54(dt, 1H, J=7.6Hz), 3.66(d, 1H, J=14.9 Hz), 3.65(d. 1H, J=14.9 Hz), 3.45(q, 1H),2.96(dd. 1H, J=17.7, 10.7 Hz), 2.91(m, 2H. J=14.2, 7.1, 7.2 Hz),2.62(dd, 1H, J=17.7, 7.5 Hz). IR(KBr, cm⁻¹)3029, 2928, 1720, 1702, 1603,1528, 1494, 1455, 1215, 895, 857, 719, 704.

EXAMPLE 35

(5S,1'S)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline(S)-mandelate

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline (2.1g, 7.50 mmol) prepared in a manner similar to that described in Example23 was dissolved in isopropyl alcohol (5 ml). The solution was added toan isopropyl alcohol solution (15 ml) of (S)-mandelic acid (1.13 g, 7.50mmol). After the mixture was stirred for 5 minutes while being refluxed,the mixture was allowed to stand at room temperature for 6 hours.Crystals precipitated were filtered under reduced pressure to give(5S-1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline(S)-mandelate (1.12 g, 2.59 mmol) as colorless crystals. Yield of(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline basedon the starting material(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline was69%. HPLC using CHIRALPAK AS (trade name) revealed that optical purityof the obtained(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline(S)-mandelate was not less than 99%. m.p. 129.5-130.0° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.43(d, 2H, J=7.5 Hz), 7.33-7.13(m, 11H),7.04(dd, 2H, J=6.4, 1.6 Hz), 4.97(s,1H), 4.48(broad s, 4H), 4.38-4.32(m,1H), 3.62(d, 1H, J=14.9 Hz), 3.52(d, 1H, J=14.9 Hz), 3.02(q, 1H, J=6.1Hz), 2.72-2.66(m, 2H), 2.54(dd, 1H, J=17.5, 7.6 Hz). IR(KBr, cm⁻¹)3482,3084, 3060, 3028, 3004, 2934, 1630, 1604, 1561, 1494, 1452, 1438, 1400,1356, 1191, 1082, 1072, 1058, 854, 750, 732, 700. α!_(D) ²⁵ +128.2°(c=0.99, CH₃ OH). Mass spectrum (FD):m/z 281(M⁺ -PhCHOHCOO). Anal.Calcd. for C₂₆ H₂₈ N₂ O₄ : C, 72.23; H, 6.53; N, 6.48%. Found: C, 72.27;H, 6.54; N, 6.41%.

EXAMPLE 36

(5R,1'R)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline(R)-mandelate

The mixture (1.18 g, 4.18 mmol) containing(5R,1'R)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline as amajor component and(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazolineprepared in a manner similar to that of Example 23 from a mother liquorof Example 35, was dissolved in isopropyl alcohol (3 ml). The solutionwas added to isopropyl alcohol (9 ml) containing (R)-mandelic acid(0.64g, 4.18 mmol). After the mixture was stirred for 5 minutes while beingrefluxed, the mixture was allowed to stand at room temperature for 6hours. Crystals precipitated were filtered under reduced pressure togive (5R,1'R)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline(R)-mandelate (1.36 g, 3.15 mmol) as colorless crystals. Yield of(5R,1'R)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline basedon the starting material(5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline ofExample 35 was 82%. HPLC using CHIRALPAK AS (trade name) revealed thatoptical purity of the obtained(5R,1'R)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline(R)-mandelate was 97.9%. m.p. 129.3-129.8° C.

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.43(d, 2H, J=7.5 Hz), 7.33-7.13(m, 11H),7.04(dd, 2H, J=6.4, 1.6 Hz), 4.97(s,1H), 4.48(broad s,4H), 4.38-4.32(m,1H), 3.62(d, 1H, J=14.9 Hz), 3.52(d, 1H, J=14.9 Hz), 3.02(q, 1H, J=6.1Hz), 2.72-2.66(m, 2H), 2.54(dd, 1H, J=17.5, 7.6 Hz). IR(KBr, cm⁻¹)3482,3084, 3060, 3028, 3004, 2934, 1630, 1604, 1561, 1494, 1452, 1438, 1400,1356, 1191, 1082, 1072, 1058, 854, 750, 732, 700. α!_(D) ²⁵ -130.8°(c=1.14, CH₃ OH). Mass spectrum (FD):m/z 281(M⁺ -PhCHOHCOO). Anal.Calcd. for C₂₆ H₂₈ N₂ O₄ : C, 72.23; H, 6.53; N, 6.48%. Found: C, 71.98;H, 6.44; N, 6.46%.

EXAMPLE 37

(A) (5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline

(5RS,1'RS)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline(100 mg) was dissolved in methylene chloride (4 ml) and trifluoroaceticacid (1 ml) were added at room temperature. After the mixture wasstirred at room temperature for 20 minutes, a 10% aqueous sodiumhydroxide was added for neutralization in an ice-water bath. After beingextracted with methylene chloride, the organic layer was dried overanhydrous magnesium sulfate. After the desiccant was filtered off, thefiltrate was concentrated under reduced pressure to give the crudedesired compound (77 mg) as a yellow liquid. The resulting yellow liquidagreed with the compound obtained in Example 23.

EXAMPLE 38

(5RS,1'RS)-3-Phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline

(5RS,1'RS)-3-Phenylmethyl-5-(1'-benzyloxycarbonylamino-2'-phenylethyl)-2-isoxazoline(9.6 mg) was dissolved in methanol (2 ml). Conc. hydrochloric acid (0.5ml) was added to the solution. The mixture was stirred for 8.25 hourswhile being refluxed. After the mixture was allowed to stand overnightat room temperature, a 10% aqueous sodium hydroxide was added, followedby extraction with methylene chloride. The organic layer was dried overanhydrous magnesium sulfate. After the desiccant was filtered off, thefiltrate was concentrated to give an oil (8.1 mg) containing the desiredcompound. The oil agreed with the compound obtained in Example 23.

EXAMPLE 39

(A)(2RS,3RS,5RS)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane

To a methanol solution (2 ml) of(5RS,1'RS)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline(10.6 mg), a 5% Pd-on-carbon catalyst (10.1 mg, 95% by weight based onsubstrate) was added. The mixture was stirred for 4 hours in a hydrogenatmosphere at atmospheric pressure. After the catalyst was filtered offunder reduced pressure, the filtrate was concentrated under reducedpressure. The resulting foamy residue (9.7 mg) was purified by silicagel thin-layer chromatography (solvent for development,chloroform/methanol=10/1).(2RS,3RS,5RS)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanewas obtained as a colorless solid (8.4 mg).

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.29-7.06(m, 10H), 5.08(d, 1H, J=9.5 Hz),3.17(d, 1H, J=10.1 Hz), 3.65(broad q, 1H), 3.01(m, 1H), 2.86(d, 2H,J=8.0 Hz), 2.77(dd, 1H, J=13.6, 4.6 Hz), 2.40(dd, 1H, J=13.6 8.5 Hz),1.55-1.39(m, 2H), 1.42(s, 9H).

(B) (2RS,3RS,5RS)-2,5-Diamino-1,6-diphenyl-3-hydroxyhexane

(2RS,3RS,5RS)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneobtained in Example 39 (A) was dissolved in methylene chloride (1 ml),and trifluoroacetic acid (0.5 ml) was added at room temperature. Afterthe mixture was stirred at room temperature for 3 hours, a 10% aqueoussodium hydroxide was added. After being extracted with methylenechloride, the mixture was dried over anhydrous sodium sulfate. After thedesiccant was filtered off, the filtrate was concentrated under reducedpressure to give the desired compound as a colorless solid (3.2 mg).

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.32-7.13(m, 10H), 3.73(dt, 1H, J=10.5,3.2 Hz), 3.11(m, 1H). 2.89(dd, 1H, J=13.2, 8.5 Hz), 2, 82(m, 2H),2.57(dd, 1H, J=13.2, 8.8 Hz), 2.51 (dd, 1H, J=13.5, 8, 3 Hz), 1.67(dt,1H, J=14.0, 2.3 Hz), 1.53(dt, 1H, J=14.0, 10.6 Hz).

EXAMPLE 40

(2S,3S,5S)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane

(5S,1'S)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline(1.0 g, 2.64 mmol) was dissolved in methanol (10 ml). A 3% Pt-on-carboncatalyst (100 mg, 10% by weight based on substrate) was added thereto,and the mixture was stirred in a hydrogen atmosphere at atmosphericpressure for 42 hours. The catalyst was removed by filtrate underreduced pressure, and then the filtrate was concentrated under reducedpressure. A foamy residue (0.99 g) containing(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneand(2S,3S.5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanewas obtained. By HPLC analysis of the residue (absolute calibrationcurve method) using CHIRALPAK AD (trade name), 0.38 g of(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane(yield: 38%) and 0.07 g of(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane(yield: 7%) were contained.

EXAMPLE 41

(2S,3S,5S)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneoxalate

(5S,1'S)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline(2.0 g, 5.26 mmol) was dissolved in an ammonia/methanol solution (3%, 20ml). A 3% Pt-on-carbon catalyst (100 mg, 5% by weight based onsubstrate) was added thereto. The mixture was stirred for 21 hours in ahydrogen atmosphere at atmospheric pressure. The catalyst was removed byfiltration under reduced pressure, and then the filtrate wasconcentrated under reduced pressure. A foamy residue (2.0 g) containing(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneand(2S,3S.5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanewas obtained. By the HPLC analysis of the residue (absolute calibrationcurve method) using CHIRALPAK AD (trade name), 1.47 g of(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane(yield: 73%) and 0.28 g of(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane(reaction yield: 14%) were contained. Oxalic acid dihydrate (633 mg,5.26 mmol) was added to the residue, the mixture was heated to dissolvedin aqueous methanol (water content: 20% v/v, 22 ml). When the mixturewas dissolved, it was cooled and crystals precipitated were collected byfiltration. The crystals were washed with aqueous methanol (watercontent: 20%) and dried under reduced pressure to give colorlesscrystals. By HPLC analysis of the crystals,(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneand(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanewere contained in the ratio of 97:3. Part of the crystals were furtherrecrystallized with aqueous methanol (water content: 20%) to give thepure desired compound in crystals, which were confirmed, by HPLC, not tocontain(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane.

m.p. 194.0-195.7° C. (decomposed).

¹ H NMR(500 MHz, (CD₃)₂ SO) δ ppm 7.33-7.13(m, 10H), 6.49(d, 1H, J=9.2Hz), 3.65(m, 1H), 3.58(m, 1H), 3.47(m, 1H), 2.86(dd, 1H, J=14.0, 6.3Hz), 2.79(dd, 1H, J=14.0, 7.2 Hz), 2.75(dd, 1H, J=13.5, 4.2 Hz),2.59(dd, 1H, J=13.5, 10.2 Hz), 1.56(m, 2H), 1.25(s,9H). In addition,there exists a rotational isomer (ppm 1.12(s)) with respect to the amidebond of tert-butoxycarbonyl group. α!_(D) ²⁵ -31.9° (c=1.33, (CH₃)₂ SO).Mass spectrum (FD):m/z 385(M⁺ -C₂ HO₄) Anal. Calcd. for the adduct C₂₅H₃₄ N₂ O₇ 0.3H₂ O: C, 62.56; H, 7.27; N, 5.84%. Found: C, 62.62; H,7.14; N, 5.81%.

EXAMPLE 42

(2S,3S,5S)-2,5-Diamino-3-hydroxy-1,6-diphenylhexane dihydrochloride

Methylene chloride and a 5% aqueous NaOH were added to(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneoxalate (11.01 g, 23.2 mmol) obtained in a manner similar to thatdescribed in Example 41, followed by extraction. The methylene chloridelayer was concentrated under reduced pressure to give a residue (8.74 g)containing(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane.2M HCI (75 ml) was added to the residue. The mixture was stirred for 1.5hours in an oil bath at 110° C. Ethanol (600 ml) was added, the mixturewas concentrated to give a residue (30.75 g). Methanol (60 ml) was addedto the residue to dissolve it. Isopropyl ether (300 ml) was addeddropwise to the solution at room temperature. Crystals precipitated werefiltered off under reduced pressure, followed by drying. The desiredcompound was obtained as colorless crystals. Yield: 7.72 g (93%).

¹ H NMR(500 MHz, (CD₃)₂ SO) δ ppm 7.97(broad s, 4H), 7.32-7.16(m, 10H),3.70(m, 1H), 3.45(m, 1H), 3.18(m 1H), 2.86(m, 4H), 1.76(m, 1H), 1.60(m,1H).

EXAMPLE 43

(A)(2S,3S,5S)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneoxalate

(5S,1'S)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline(3.69 g. 7.88 mmol) obtained in a manner similar to that described inExample 6 was dissolved in methanol(40 ml). To the solution, ammoniumacetate (1.21 g, 15.8 mmol) and acetic acid (1.0 ml) were added. A 3%Pt-on-carbon catalyst (300 mg, 8.1% by weight based on substrate) wasadded thereto. The mixture was stirred for 24 hours in a hydrogenatmosphere at atmospheric pressure. The catalyst was removed byfiltration under reduced pressure, and the filtrate was concentratedunder reduced pressure. The resulting oil (6.56 g) was extracted withmethylene chloride (50 ml) and an aqueous 10% NaOH (50 ml). The organiclayer was washed with water, then dried over anhydrous magnesiumsulfate. The desiccant was filtered off and the filtrate wasconcentrated under reduced pressure to give a foamy residue (4.0 g)containing(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneand(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane.Analysis by HPLC revealed that the ratio of(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneto(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanewas 6:1. To the thus-obtained product, oxalic acid dihydrate (993 mg,7.88 mmol) was added, and the resulting mixture was heated to dissolvein aqueous methanol (water content: 20 v/v%, 50 ml). When the mixturewas dissolved, it was cooled and crystals precipitated were collected byfiltration. The crystals were washed with aqueous methanol (watercontent: 20%, 10 ml×3, 3 ml×3) then dried under reduced pressure. Thecrude crystals (2.58 g) were confirmed, by HPLC, to contain(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneand(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanein the ratio of 97:3. The crude crystals were recrystallized fromaqueous methanol (water ratio: 20 v/v%, 35 ml) in a manner similar tothat as described above to give the desired compound as colorlesscrystals. Yield: 2.06 g (55%). This compound was identical to thatobtained in Example 41.(2S,3S.5R)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanewas not detected by HPLC.

(B)(2S,3S,5S)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane

(2S,3S,5S)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneoxalate (500 mg, 1.05 mmol) obtained in Example 43 (A) was suspended intoluene (5 ml). An aqueous solution (5 ml) of NaOH (200 mg) was addedthereto and the mixture was vigorously stirred, then separated. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate. The desiccant was filtered off, and the filtrate wasconcentrated to give the desired compound as colorless crystals. Yield:340 mg (84%). ¹ H NMR(500 MHz, CDCl₃) δ ppm 7.29-7.06(m, 10H), 5.08(d,1H, J=9.5 Hz), 3.77(d, 1H, J=10.1 Hz), 3.65(broad q, 1H), 3.01 (m, 1H),2.86(d, 2H, J=8.0 Hz), 2.77(dd, 1 H, J=1 3.6, 4.6 Hz), 2.40(dd, 1H,J=13.6, 8.5 Hz), 1.55-1.39(m 2H), 1.42(s, 9H).

EXAMPLE 44

(2S,3S,5S)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneoxalate

(5S,1'S)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline(250 mg, 0.66 mmol) prepared in a manner similar to that as described inExample 6 was dissolved in methanol(10 ml). Acetic acid (0.25 ml) wasadded to the solution. A 3% Pt-on-carbon catalyst (25 mg, 10% by weightbased on substrate) was added to the mixture. The mixture was stirredfor 27 hours in a hydrogen atmosphere at atmospheric pressure. Thecatalyst was removed by filtration under reduced pressure, and thefiltrate was concentrated under reduced pressure. The resulting oil (390mg) was dissolved in ethyl acetate (50 ml), washed successively withsaturated aqueous sodium bicarbonate and saturated brine, and then driedover anhydrous magnesium sulfate. After the desiccant was filtered off,the filtrate was concentrated under reduced pressure to obtain a foamyresidue (260 mg) containing(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneand(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane.Analysis by ¹ H NMR revealed that the ratio of(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneto(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanewas 10:1. To the residue, oxalic acid dihydrate (83 mg, 0.66 mmol) wasadded, and the resulting mixture was dissolved with heat whilerefluxing. Diisopropyl ether (15 ml) was added, and the mixture wascooled. The crystals precipitated were collected by filtration and weredried under reduced pressure to give the desired compound as colorlesscrystals. Yield: 216 mg (69%). Analysis by HPLC revealed that the ratioof(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneand(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanewas 97:3.

EXAMPLE 45

(2S,3S,5S)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneoxalate

(5S,1'S)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline(1.0 g, 2.62 mmol) prepared in a manner similar to that as described inExample 6 was dissolved in methanol(10 ml). Conc. aqueous ammonia (25%,2 ml) was added to the solution. A 3% Pt-on-carbon catalyst (20 mg, 2%by weight based on substrate) was added to the mixture. The mixture wasstirred for 96 hours in a hydrogen atmosphere at atmospheric pressure.The catalyst was removed by filtration under reduced pressure, and thefiltrate was concentrated under reduced pressure. By HPLC analysis ofthe residue,(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneand(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanewere contained in the ratio of 5:1. To the oil, oxalic acid dihydrate(330 mg, 2.62 mmol) was added, and the resulting mixture was heated todissolve in aqueous methanol (water content: 20 v/v%, 12 ml). When themixture was dissolved, it was cooled and crystals precipitated werecollected by filtration. Yield: 510 mg (41%). The crystals wereconfirmed, by HPLC, to contain(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneand(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanein the ratio of 97:3.

EXAMPLE 46

(2S,3S,5S)-2-tert-Butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane

(5S,1'S)-3-Phenylmethyl-5-(1'-tert-butoxycarbonylamino-2'-phenylethyl)-2-isoxazoline(500 mg, 1.31 mmol) prepared in a manner similar to that described inExample 6 was dissolved in an ammonia/methanol solution (3%, 10 ml). A5% Pd-on-carbon catalyst (50 mg, 10% by weight based on substrate) wasadded to the solution. The mixture was stirred for 72 hours in ahydrogen atmosphere at atmospheric pressure. The catalyst was removed byfiltration under reduced pressure, and the filtrate was concentratedunder reduced pressure to give a foamy residue containing (2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane and(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexane.Analysis by HPLC revealed that the ratio of(2S,3S,5S)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexaneto(2S,3S,5R)-2-tert-butoxycarbonylamino-3-hydroxy-5-amino-1,6-diphenylhexanewas 3:1.

EXAMPLE 47

(2RS,3RS,5RS)-2,5-Diamino-1,6-diphenyl-3-hydroxyhexane and(2RS,3RS,5SR)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane

A crude form (77 mg) of (5RS,1'RS)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline obtainedin Example 37 was dissolved in diethyl ether (6 ml). Lithium aluminumhydride (55 mg) was added to the solution. The mixture was refluxed withheat for 6 hours and then cooled, after which a 10% aqueous sodiumhydroxide was added thereto. The mixture was extracted with diethylether and methylene chloride respectively. The organic layer werecombined together and concentrated under reduced pressure to give acrude pale yellow oil (77 mg) of a mixture of(2RS,3RS,5RS)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane and(2RS,3RS5SR)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane. The oil waspurified by silica gel thin-layer chromatography (solvent fordevelopment, chloroform:methanol:isopropylamine=96:2:2) to give(2RS,3RS,5RS)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane (39 mg) and(2RS,3RS,5SR)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane (27 mg) both aswhite solids. (2RS,3RS,5RS)-2,5-Diamino-1,6-diphenyl-3-hydroxyhexane:

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.32-7.13(m, 10H), 3.73(dt, 1H, J=10.5,3.2 Hz), 3.11(m, 1H). 2.89(dd, 1H, J=13.2, 8.5 Hz), 2.82(m, 2H).2.57(dd, 1H, J=13.2, 8.8 Hz), 2.51 (dd, 1H, J=13.5, 8.3 Hz), 1.67(dt,1H, J=14.0, 2.3 Hz), 1.53(dt, 1H, J=14.0, 10.6 Hz).(2RS,3RS,5RS)-2,5-Diamino-1,6-diphenyl-3-hydroxyhexane:

¹ H NMR(500 MHz, CDCl₃) δ ppm 7.33-7.13(m, 10H), 3.77(m, 1H), 3.43(m,1H), 2.85(m, 2H), 2.80(dd, 1H, J=13.4, 5.1 Hz), 2.61 (dd, 1H, J=13.4, 8,9 Hz), 2.47(dd, 1H, J=14.3, 10.3 Hz), 1.79(ddd, 1H, J=14.1, 9.6, 3.1Hz), 1.52(ddd, 1H, J=14.1, 7.8, 2.9 Hz).

EXAMPLE 48

(2S,3S,5S)-2-Acetylamino-3-hydroxy-5-amino-1,6-diphenylhexane and(2S,3S,5R)-2-acetylamino-3-hydroxy-5-amino-1,6-diphenylhexane

(5S, 1'S)-3-Phenylmethyl-5-(1'-acetylamino-2'-phenylethyl)-2-isoxazoline(250 mg, 0.78 mmol) prepared in a manner similar to that described inExample 17 was dissolved in methanol (10 ml), and acetic acid (0.25 ml)was added thereto. A 3% Pt-on-carbon catalyst (25 mg, 10% by weightbased on substrate) was added to the mixture. The resulting mixture wasstirred for 5 days in a hydrogen atmosphere at atmospheric pressure. Thecatalyst was removed by filtration under reduced pressure, and thefiltrate was concentrated under reduced pressure. The resulting oil wasdissolved in ethyl acetate (50 ml). The solution was washed withsaturated sodium bicarbonate and then with saturated brine, and driedover anhydrous magnesium sulfate. After the desiccant was filtered off,the filtrate was concentrated under reduced pressure to give an oil (250mg). The oil was purified by silica gel column chromatography (solventfor elution, chloroform: methanol=7:1) to give the mixture of (2S, 3S,5S)2-acetylamino-3-hydroxy-5-amino-1,6-diphenylhexane and(2S,3S,5R)-2-acetylamino-3-hydroxy-5-amino-1,6-diphenylhexane as acolorless solid. Yield: 150 mg.(2S,3S,5S)-2-Acetylamino-3-hydroxy-5-amino-1,6-diphenylhexane in themixture:

1H NMR(500 MHz, CDCl₃) δ ppm 7.30-7.07(m, 10H), 6.02(d, 1H, J=9.3 Hz),4.03(m, 1H), 3.79(m, 1H), 3.03(m, 1H), 2.86(d, 2H, J=7.7 Hz), 2.79(dd,1H, J=13.6, 4.9 Hz), 2.43(dd, 1H, J=13.6, 8.5 Hz), 1.98(s, 3H), 1.54(dt,1H, J=14.2, 2.0 Hz), 1.37(dt, 1H, J=14.2, 11.1 Hz).

EXAMPLE 49

(2S,3S,5S)-2-N,N-Dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane

(5S,1'S)-3-Phenylmethyl-5-(1'-N,N-dibenzylamino-2'-phenylethyl)-2-isoxazoline(9.2 g, 20 mmol) obtained in Example 21 was dissolved in diisopropylether (92 ml). Lithium aluminum hydride (3.8 g, 100 mmol) was added tothe solution under nitrogen. The mixture was stirred at 60° C. for 5hours and then cooled to room temperature. A 25% aqueous sodiumhydroxide (120 g), diisopropyl ether (200 ml), and water (50 ml) wereadded to the mixture. Solid mass was removed by filtration, and thefiltrate was extracted. Then, the organic layer was concentrated underreduced pressure to give an oil (9.2 g). The oil (4.0 g) was separatedand purified by silica gel column chromatography (solvent for elution,hexane:ethyl acetate=1:1) to give the desired compound as colorlesscrystals. Yield: 2.32 g. ¹ HNMR(500 MHz, CDCl₃) δ ppm 7.33-7.09(m, 20H),4.17(d, 2H, J=13.7 Hz), 3.67(m, 1H), 3.46(d, 2H, J=13.7 Hz), 3.05(dd,1H, J=13.3, 4.6 Hz), 2.98(m, 1H), 2.94(dd, 1H, J=13.3, 9.1 Hz), 2.70(dd,1H, J=13.3, 5.0 Hz), 2.62(m, 1H), 2.47(dd, 1H, J=13.3, 7.8 Hz), 1.63(m,1H), 1.26(m, 1H).

EXAMPLE 50

(2S,3S,5S)-2-N,N-Dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane

(5S,1'S)-3-Phenylmethyl-5-(1'-N,N-dibenzylamino-2'-phenylethyl)-2-isoxazoline(100 mg, 0.217 mmol) obtained in Example 21 was dissolved in anammonia/ethanol solution (3.4%, 20 ml). A 3% Pt-on-carbon catalyst (100mg) was added to the solution. The resulting mixture was stirred for 20hours at atmospheric pressure under hydrogen atmosphere. The catalystwas removed by filtration, followed by washing with diisopropyl ether (5ml). The filtrate was concentrated under reduced pressure to give a palepink oil (86 mg), the entirety of which was purified by silica gelthin-layer chromatography (solvent for development,chloroform:methanol:isopropylamine=96:2:2) to give the desired compound(yield: 52 mg) as colorless oil. The thus obtained compound agreed withthe compound obtained in Example 49.

INDUSTRIAL APPLICABILITY

The present invention provides novel 2-isoxazoline derivativesrepresented by formula 1!, 2! or 3! or acid addition salts thereof,which are useful intermediates for2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives which in turn serveas intermediates in the synthesis of medicines such as retrovirusprotease inhibitors. The invention also provides methods for preparingsuch derivatives as well as methods for preparing2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives using the2-isoxazoline derivatives. The methods of the invention are industriallyvery useful because heavy-metal and special reagents are not used andvery low temperature reaction conditions are not required.

We claims:
 1. A method of preparing an acid addition salt of a2-isoxazoline derivative represented by formula (2) or formula (3) whichcomprisesoptically resolving a mixture of 2-isoxazoline derivativesrepresented by formula (2) and formula (3) or a mixture of the acidaddition salt thereof and an optically active acid: ##STR9## wherein Phrepresents phenyl; and each of R¹ and R² independently representshydrogen, acyl, alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl, alkyl,arylalkyl, aryl, alkylsulfonyl, arylalkylsulfonyl, or arylfulfonyl, orR₁ and R² are linked to each other to form divalent acyl.
 2. The methodaccording to claim 1 wherein R¹ and R² are each hydrogen.
 3. The methodaccording to claim 2, wherein the optically active acid is (S)-mandelicacid, and the compound to be obtained is(5S,1'S)-3-phenylmethyl-5-(1'-amino-2'-phenylethyl)-2-isoxazoline(S)-mandelate.
 4. The method according to claim 2, wherein the opticallyactive acid is (R)-mandelic acid, and the compound to be obtained is(5R,1'R)-3-phenylmethyl-5-(1'amino-2'-phenylethyl)-2-isoxazoline(R)-mandelate.